Combination therapy of ARM and natural killer cells

Abstract

Among other things, the present disclosure provides techniques involving immune cells and antibody recruitment molecules. In some embodiments, the immune cells are memory-like natural killer cells. In some embodiments, the provided techniques are particularly useful for treating conditions, disorders, or diseases such as cancer. In some embodiments, the provided techniques offer a high level of efficacy. In some embodiments, the provided techniques offer fewer or less severe side effects associated with natural killer cell therapy.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority of U.S. Application No. 62 / 783,036, filed on December 20, 2018, the entire content of which is incorporated herein by reference. Background of the Invention

[0003] Immune system activity can be used to prevent or treat various conditions, disorders, and diseases, including cancer. Summary of the Invention

[0004] Natural killer (NK) cells are capable of inducing cell death in a variety of targets (e.g., diseased cells such as cancer cells). Among other things, NK cells (e.g., in vitro - expanded and / or pre - activated NK cells) are being developed for cancer treatment. In some embodiments, the present disclosure encompasses the recognition that NK cell therapy can be significantly improved by agents that assist and / or facilitate NK cell recognition of targets. In some embodiments, the present disclosure provides technologies (e.g., methods, compositions, etc.) comprising NK cells and such agents. In particular, in some embodiments, the present disclosure provides technologies comprising NK cells and antibody - recruitment molecules (ARMs), the antibody - recruitment molecules comprising (i) an antibody - binding portion that can bind to one or more antibodies or fragments thereof, (ii) a target - binding portion that can bind to a cell, and optionally (iii) a linker portion that connects the antibody - binding portion to the target - binding portion.

[0005] In some embodiments, an ARM can significantly improve the efficiency of NK cell therapy, e.g., by facilitating NK cell recognition of target cells. In some embodiments, an ARM can enhance the interaction between NK cells and their target cells, and / or promote target cell death induced by NK cells. In some embodiments, an ARM promotes the activation of NK cells, e.g., by recruiting antibodies to target cells, and then the antibodies can recruit and activate NK cells.

[0006] Additionally or alternatively, in some embodiments, the ARM reduces and / or delays the onset of one or more side effects of NK cell therapy, e.g., by directing NK cells to target cells and reducing off-target effects. In some embodiments, NK cells are typically activated, enriched, and / or expanded prior to administration to a subject. Such pre-activated NK cells are more potent and may be necessary for effective killing of target cells; however, due to their activation, these cells may cause significantly more side effects, e.g., killing of unintended cells. Among other things, the present disclosure provides techniques by which the ARM can direct NK cells to target cells and reduce side effects and toxicities associated with NK cell therapy. Additionally, in view of the reduced off-target effects, in some embodiments, more activated NK cells can be utilized to further improve treatment efficiency.

[0007] Among other things, the antibody-binding portion (referred to in some embodiments as the antibody-binding terminus (ABT)) can bind an antibody (or a fragment thereof). In some embodiments, the antibody-binding portion binds to the variable region. In some embodiments, the antibody-binding portion binds to the Fab region. In some embodiments, the antibody-binding portion (“universal ABT” or “uABT”) can (among other things) recruit antibodies (or fragments thereof) having various antigen specificities, e.g., by binding to the Fc region. In some embodiments, the use of uABT can avoid the dependence on a particular antibody population and adverse effects that may be caused by individual variations in a particular antibody population. In some embodiments, uABT is capable of preferentially recruiting IgG1, IgG2, and / or IgG4. In some embodiments, the recruitment of antibodies (e.g., IgG subclasses) is limited by the dose of the ARM administered and / or is not limited by the level of antibodies having a particular Fab region in an individual. In some embodiments, the ABT binds and recruits endogenous antibodies. In some embodiments, uABT preferably binds IgG molecules more than human IgA or IgM. Typically, after being bound by the antibody-binding portion, the antibody is still able to perform one or more of its immunological activities, e.g., interact with NK cells, which can result in the killing of target cells by the NK cells.

[0008] Typically, the target-binding portion (referred to in some embodiments as the target-binding terminus (TBT)) can confer specificity of the ARM for its target (e.g., a diseased target cell) by binding, e.g., to an entity (e.g., a cell surface receptor) that differentiates the target from non-targets (e.g., diseased cells from other cell types).

[0009] Among other things, an ARM can effect target - specific antibody (e.g., endogenous antibody, administered antibody, etc.) recruitment via ABT, and / or trigger, generate, encourage, and / or enhance NK - cell - related immune activities, e.g., NK - cell killing of target cells. A variety of techniques (e.g., assays, reagents, methods, etc.) can be used to evaluate antibody - binding moieties, target - binding moieties, and ARMs, and can be used in accordance with this disclosure.

[0010] In some embodiments, an ARM comprises:

[0011] an antibody - binding moiety,

[0012] a target - binding moiety, and

[0013] an optional linker moiety,

[0014] wherein the antibody - binding moiety can bind to the Fab region of an antibody.

[0015] In some embodiments, an ARM comprises:

[0016] an antibody - binding moiety,

[0017] a target - binding moiety, and

[0018] an optional linker moiety,

[0019] wherein the antibody - binding moiety can bind to the Fc region of an antibody.

[0020] In some embodiments, an ARM comprises:

[0021] an antibody - binding moiety,

[0022] a target - binding moiety, and

[0023] an optional linker moiety,

[0024] wherein the antibody - binding moiety can bind to two or more antibodies having different Fab regions.

[0025] In some embodiments, the antibody - binding moiety (e.g., a universal antibody - binding moiety) binds to the Fc region of an antibody. In some embodiments, the antibody - binding moiety (e.g., a universal antibody - binding moiety) binds to the conserved Fc region of an antibody. In some embodiments, the antibody - binding moiety binds to the Fc region of an IgG antibody.

[0026] In some embodiments, an agent (e.g., an ARM) of this disclosure is a compound having the structure of Formula I:

[0028] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the agent is a compound of Formula I or a salt thereof.

[0029] In some embodiments, the agent is a compound of Formula I-a:

[0031] or a salt thereof, wherein each variable is as defined and described in the present disclosure. In some embodiments, the agent (e.g., ARM) is a compound of Formula I-a or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula I-a.

[0032] In some embodiments, the agent is a compound of Formula I-b:

[0034] or a salt thereof, wherein each variable is as defined and described in the present disclosure. In some embodiments, the agent (e.g., ARM) is a compound of Formula I-b or a pharmaceutically acceptable salt thereof. In some embodiments, the provided compound of Formula I is a compound of Formula I-b.

[0035] In some embodiments, the agent (e.g., ARM) is a compound having the structure of Formula II:

[0037] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the agent is a compound of Formula II or a salt thereof. In some embodiments, the compound of Formula I is a compound of Formula II or a salt thereof. In some embodiments, the compound having the structure of Formula I-a is a compound of Formula II.

[0038] In some embodiments, the agent (e.g., ARM) is a compound having the structure of Formula III:

[0040] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the agent is a compound of Formula III or a salt thereof. In some embodiments, the compound of Formula I is a compound of Formula III or a salt thereof. In some embodiments, the compound having the structure of Formula I-b is a compound of Formula III.

[0041] The combination of NK cells and an agent (e.g., ARM) of the present disclosure can be particularly effective in treating various conditions, disorders, or diseases including cancer. In some embodiments, the present disclosure provides the following combinations, which comprise:

[0042] An expanded, enriched, and / or pre-activated population of natural killer cells; and

[0043] An antibody recruitment molecule (ARM), wherein:

[0044] The ARM includes an antibody-binding portion that can bind to one or more antibodies or fragments thereof, a target-binding portion that can bind to a target entity, and optionally a linker portion that connects the antibody-binding portion to the target-binding portion.

[0045] In some embodiments, the present disclosure provides methods for inducing cell death, inhibiting cell growth, and / or reducing the number of cells in a system, comprising administering to the system:

[0046] One or both of the following:

[0047] A plurality of natural killer cells; and

[0048] An antibody recruitment molecule (ARM),

[0049] wherein the ARM includes an antibody-binding portion that can bind to one or more antibodies or fragments thereof, a target-binding portion that can bind to cells, and optionally a linker portion that connects the antibody-binding portion to the target-binding portion;

[0050] The system is then exposed to both, and the number of cells in the system is reduced compared to the situation where the natural killer cells and the antibody recruitment molecule are absent.

[0051] Those skilled in the art will understand that the techniques provided are applicable to various systems as described herein. For example, in some embodiments, the system is an organism. In some embodiments, the system is a subject. In some embodiments, the system is a human. In some embodiments, the system is a patient. In some embodiments, the system is a non-human animal. In some embodiments, the system is a non-human animal that can be used as a disease model. In some embodiments, the system is an organ. In some embodiments, the system is a tissue. In some embodiments, the system is an in vivo system. In some embodiments, the system is an ex vivo system. In some embodiments, the system is an in vitro system. In some embodiments, the system is or includes a cell culture.

[0052] In some embodiments, the present disclosure provides methods for treating cancer, comprising administering to a subject having cancer:

[0053] One or both of the following:

[0054] A plurality of natural killer cells; and

[0055] An antibody recruitment molecule (ARM),

[0056] wherein the ARM includes an antibody-binding portion that can bind to one or more antibodies or fragments thereof, a target-binding portion that can bind to cancer cells, and optionally a linker portion that connects the antibody-binding portion to the target-binding portion.

[0057] The subject is then exposed to both of these.

[0058] In some embodiments, the subject is a human. In some embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a non-human animal that can be used as a disease model.

[0059] In some embodiments, the number of cancer cells in the subject is reduced compared to the situation where natural killer cells and antibody recruitment molecules are absent. In some embodiments, the growth of cancer cells in the subject is reduced compared to the situation where natural killer cells and antibody recruitment molecules are absent. In some embodiments, the proliferation of cancer cells in the subject is reduced compared to the situation where natural killer cells and antibody recruitment molecules are absent. In some embodiments, the volume of cancer cells in the subject is decreased compared to the situation where natural killer cells and antibody recruitment molecules are absent.

[0060] In some embodiments, the present disclosure provides a method for treating cancer, which comprises administering to a subject suffering from cancer:

[0061] A plurality of natural killer cells; and

[0062] An antibody recruitment molecule,

[0063] wherein the ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to cancer cells, and optionally a linker portion that connects the antibody binding portion to the target binding portion.

[0064] In some embodiments, the present disclosure provides a method for reducing the toxicity or side effects of a treatment using natural killer cells, which comprises administering to a subject:

[0065] A plurality of natural killer cells; and

[0066] An antibody recruitment molecule,

[0067] wherein the ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to the target entity of the treatment, and optionally a linker portion that connects the antibody binding portion to the target binding portion.

[0068] In some embodiments, the present disclosure provides an improvement in a method for treating a subject by administering a plurality of natural killer cells, the improvement further comprising administering an antibody recruitment molecule (ARM), wherein the ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to a target entity, and optionally a linker portion that connects the antibody binding portion to the target binding portion.

[0069] An agent of the present disclosure (e.g., ARM) can be administered before, simultaneously with, and / or after NK cells (e.g., expanded, enriched, and / or pre-activated NK cells). BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 . The provided technology has low toxicity. A. Frequency of dead NK cells. B. Frequency of dead NK cells normalized to DMSO-treated control.

[0071] Figure 2 . The provided technology can effectively kill cancer cells. A. Frequency of dead SUDHL-4 cells in NK-SUDHL-4 co-culture. B. Frequency of dead SUDHL-4 cells in NK-SUDHL-4 co-culture normalized to DMSO-treated control.

[0072] Figure 3 . The provided technology can reduce the number of plasma cells.

[0073] Figure 4 . The provided technology does not cause unwanted NK cell fratricide or causes a low level of unwanted NK cell fratricide. DETAILED DESCRIPTION

[0074] 1. General description of certain embodiments of the present invention:

[0075] As described above, in some embodiments, the present disclosure provides technologies for inducing cell death, inhibiting cell growth, and / or reducing cell number in a system. Alternatively or additionally, in some embodiments, the present disclosure provides technologies for treating cancer and / or for reducing the toxicity and / or side effects of cell immunotherapy (e.g., NK cell therapy).

[0076] In some embodiments, the present disclosure utilizes an ARM agent in conjunction with a cell immunotherapy such as NK cell therapy (e.g., involving in vitro expansion of NK cells). In some embodiments, one or more ARM agents as described herein are administered to a subject who has, is, or will receive NK cell therapy, or otherwise has or will have a population of NK cells targeting a target site (e.g., a tumor). Conversely, in some embodiments, cell immunotherapy (e.g., NK cell therapy) is administered to a subject who has, is, or will receive an ARM agent therapy as described herein.

[0077] In some embodiments, the present disclosure uses an ARM agent comprising an antibody-binding portion that can bind to an antibody (or a fragment thereof) having different Fab structures. In particular, in some embodiments, the relevant ARM agent comprises an antibody-binding portion that binds to the Fc region of an antibody; in certain embodiments, this binding to the Fc region of the antibody does not interfere with one or more immunological activities of the antibody, e.g., interacting with an Fc receptor (e.g., CD16a), recruiting effector cells (such as NK cells for ADCC), etc. As understood by those skilled in the art, the techniques (agents, compounds, compositions, methods, etc.) provided by the present disclosure that comprise a uABT can offer various advantages. For example, the techniques provided can utilize antibodies with different Fab regions in the immune system to avoid or minimize the adverse effects of antibody variations in the patient population and can trigger and / or enhance the immunological activity against a target, e.g., killing target diseased cells such as cancer cells.

[0078] In some embodiments, the techniques of the present disclosure can be used to recruit antibodies and NK cells to various targets (e.g., cancer cells). In some embodiments, the techniques provided can be used to modulate the immunological activity (such as ADCC involving NK cells) against a target (diseased cells, foreign objects or entities, etc.). In some embodiments, the techniques provided can be used to modulate the activity of NK cells against target cells (e.g., diseased cells such as cancer cells). In some embodiments, the target-binding portion is an inhibitor portion. In some embodiments, the target-binding portion is an enzyme inhibitor portion. In some embodiments, the target-binding portion binds to a cell surface entity (e.g., protein, carbohydrate, lipid, etc.).

[0079] In some embodiments, an agent (e.g., an ARM) comprises:

[0080] an antibody-binding portion,

[0081] a target-binding portion, and

[0082] an optional linker portion,

[0083] wherein the antibody-binding portion can bind to the Fab region.

[0084] In some embodiments, an agent (e.g., an ARM) comprises:

[0085] an antibody-binding portion,

[0086] a target-binding portion, and

[0087] an optional linker portion,

[0088] wherein the antibody-binding portion can bind to the Fc region.

[0089] In some embodiments, an agent (e.g., an ARM) comprises:

[0090] an antibody-binding portion,

[0091] a target-binding portion, and

[0092] an optional linker portion,

[0093] wherein the antibody-binding portion can bind two or more antibodies having different Fab regions.

[0094] In some embodiments, an agent for practicing the techniques of the present disclosure comprises two or more antibody-binding portions. In some embodiments, useful agents comprise two or more target-binding portions.

[0095] The antibody-binding portion can interact with any part of the antibody. In some embodiments, the antibody-binding portion binds to the Fc region of the antibody. In some embodiments, the antibody-binding portion binds to a conserved Fc region of the antibody. In some embodiments, the antibody-binding portion binds to the Fc region of an IgG antibody. As will be understood by those skilled in the art, various antibody-binding portions, linkers, and target-binding portions can be used in accordance with the present disclosure. Among other things, as demonstrated in the Examples, in some embodiments, the present disclosure provides antibody-binding portions, linkers, and target-binding portions and combinations thereof that are particularly useful and effective for constructing ARM molecules to recruit antibodies to target cells and / or trigger, generate, encourage, and / or enhance immune system activity against target cells (e.g., diseased cells such as cancer cells).

[0096] In some embodiments, the antibody-binding portion can bind to an Fc region that binds to an Fc receptor (e.g., FcγRIIIa, CD16a, etc.). In some embodiments, the provided portion and / or agent (e.g., compounds / ARMs of various formulas as described in the present disclosure) comprises an antibody-binding portion that binds to a complex comprising an Fc region and an Fc receptor. In some embodiments, the complex comprises:

[0097] an agent, which comprises:

[0098] an antibody-binding portion,

[0099] a target-binding portion, and

[0100] an optional linker portion,

[0101] an Fc region, and

[0102] an Fc receptor,

[0103] The antibody-binding portion of the agent can bind two or more antibodies having different Fab regions.

[0104] In some embodiments, the Fc region is the Fc region of an endogenous antibody of the subject. In some embodiments, the Fc region is the Fc region of an exogenous antibody. In some embodiments, the Fc region is the Fc region of the administered agent. In some embodiments, the Fc receptor belongs to the diseased cells of the subject. In some embodiments, the Fc receptor belongs to the cancer cells of the subject.

[0105] In certain embodiments, the agent (e.g., ARM) has Formula I:

[0107] or a pharmaceutically acceptable salt thereof, wherein:

[0108] ABT is an antibody-binding portion;

[0109] L is a bivalent linker portion that connects ABT to TBT; and

[0110] TBT is a target-binding portion.

[0111] In some embodiments, ABT is a universal antibody-binding portion.

[0112] In some embodiments, the antibody-binding portion comprises one or more amino acid residues. In some embodiments, the antibody-binding portion is or comprises a peptide portion. In some embodiments, the antibody-binding portion is or comprises a cyclic peptide portion. In some embodiments, such antibody-binding portions comprise one or more natural amino acid residues. In some embodiments, such antibody-binding portions comprise one or more non-natural amino acid residues.

[0113] In some embodiments, the amino acid has a structure of Formula A-I:

[0114] NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH,

[0115] A-I

[0116] or a salt thereof, wherein:

[0117] R a1 、R a2 、R a3 are each independently -L a -R';

[0118] L a1 and L a2 are each independently La ;

[0119] Each L a is independently a covalent bond or is selected from C 1 -C 20 -aliphatic or C with 1-5 heteroatoms 1 -C 20 an optionally substituted divalent group of heteroaliphatic, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -,-Cy-,-O-,-S-,-S-S-,-N(R’)-,-C(O)-,-C(S)-,-C(NR’)-,-C(O)N(R’)-,-N(R’)C(O)N(R’)-,-N(R’)C(O)O-,-S(O)-,-S(O) 2 -,-S(O) 2 -N(R’)-,-C(O)S- or -C(O)O-;

[0120] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 -alicyclic ring, C 6-20 -aryl ring, 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0121] Each R' is independently -R, -C(O)R, -CO 2 -R, or -SO 2 -R;

[0122] Each R is independently -H or an optionally substituted group, said optionally substituted group being selected from C 1-30 -aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 -heteroaliphatic, C 6-30 -aryl, C 6-30 -aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 -aryl heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0123] two R groups are optionally and independently joined together to form a covalent bond, or:

[0124] Two or more R groups on the same atom optionally and independently together with said atom form an optionally substituted monocyclic, bicyclic or polycyclic ring of 3 to 30 members, said monocyclic, bicyclic or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to said atom; or

[0125] Two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted monocyclic, bicyclic or polycyclic ring of 3 to 30 members, said monocyclic, bicyclic or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms.

[0126] In some embodiments, the antibody binding portion is a cyclic peptide portion. In some embodiments, the compound (e.g., agent, ARM) is of formula I-a:

[0128] or a salt thereof, wherein:

[0129] Each Xaa is independently an amino acid residue;

[0130] t is 0 - 50;

[0131] z is 1 - 50;

[0132] L is a linker portion;

[0133] TBT is a target binding portion;

[0134] Each R c is independently -L a -R’;

[0135] a and b are each independently 1 - 200;

[0136] Each L a is independently a covalent bond or is selected from C 1 -C 20 aliphatic or C having 1 - 5 heteroatoms 1 -C 20 heteroaliphatic optionally substituted divalent groups, wherein one or more methylene units of said groups are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, or -C(O)O-;

[0137] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 alicyclic ring, C 6-20 aryl ring, 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon;

[0138] Each R' is independently -R, -C(O)R, -CO 2 R, or -SO 2 R;

[0139] Each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 arylalkyl, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or

[0140] two R groups optionally and independently together form a covalent bond, or:

[0141] two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom; or

[0142] two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms.

[0143] In some embodiments, a is 1. In some embodiments, b is 1. In some embodiments, a is 1 and b is 1, and the compound of formula I-a has

[0144] In some embodiments, each amino acid residue, such as each Xaa in formula I-a, is independently an amino acid residue having the structure of formula A-I. In some embodiments, each Xaa independently has -N(R a1 )-L a1 -C(Ra2 )(R a3 )-L a2 -CO- structure. In some embodiments, two or more side chains of an amino acid residue (e.g., in a compound of formula I-a), such as the R a2 or R a3 of one amino acid residue and the R a2 or R a3 ) of another amino acid residue optionally form a bridge together (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.). For example, in some embodiments, two cysteine residues form an -S-S- bridge, as commonly observed in natural proteins. In some embodiments, the formed bridge has the structure of L b , where L b is L as described in the present disclosure a . In some embodiments, each end of L b is independently connected to the backbone atoms of the cyclic peptide (e.g., the ring atoms of the ring formed by -(Xaa) z - in formula I-a). In some embodiments, L b contains an R group (e.g., when a methylene unit of L b is replaced by -C(R) 2 - or -N(R)-), where the R group together with the R group attached to the backbone atom (e.g., R a1 , R a2 , R a3 , etc., if it is R) and the intervening atoms form a ring. In some embodiments, L b is connected to the ring through the side chain of an amino acid residue (e.g., Xaa in formula I-a), such as the ring formed by -(Xaa) z - in formula I-a. In some embodiments, such side chains contain an amino group or a carboxylic acid group.

[0145] In some embodiments,

[0146] In certain embodiments, a compound (e.g., a medicament, an ARM, etc.) has formula II:

[0148] or a pharmaceutically acceptable salt thereof, wherein:

[0149] R 1 , R 3 and R 5 are each independently hydrogen or an optionally substituted group, and the optionally substituted group is selected from C 1-6Aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0150] R 1 and R 1 'optionally together with the intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocarbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0151] R 3 and R 3’ optionally together with the intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocarbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0152] R 5 group and the R 5’ group attached to the same carbon atom optionally together with the intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocarbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0153] Two R 5 groups optionally together with the intervening atoms form a C 1-10 optionally substituted divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -, or -Cy 1 -, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0154] R 1’ 、R 3’ and R 5’ are each independently hydrogen or optionally substituted C 1-3 aliphatic;

[0155] R 2 、R 4 and R 6Each is independently hydrogen or an optionally substituted C 1-4 aliphatic, or:

[0156] R 2 and R 1 optionally together with the intervening atoms form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0157] R 4 and R 3 optionally together with the intervening atoms form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

[0158] R 6 the group and the adjacent R 5 group optionally together with the intervening atoms form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0159] L 1 is a linking

[0160] L 2 is a covalent bond or a C 1-30 optionally substituted divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 10 methylene units of the chain are independently and optionally substituted with -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -,

[0161] TBT is a target binding moiety; and

[0162] m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0163] In some embodiments, the antibody binding moiety is or comprises a peptide moiety. In some embodiments, the compound (e.g., a medicament, an ARM, etc.) has a structure of Formula I-b:

[0165] or a salt thereof, wherein:

[0166] each Xaa is independently an amino acid residue;

[0167] each z is independently 1 - 50;

[0168] each L is independently a linker moiety;

[0169] TBT is a target binding moiety,

[0170] Each R c is independently -L a -R';

[0171] a1 and a2 are each independently 0 or 1, with at least one of a1 and a2 not being 0;

[0172] a and b are each independently 1 - 200;

[0173] Each L a is independently a covalent bond or is selected from C 1 -C 20 aliphatic or C having 1 - 5 heteroatoms 1 -C 20 optionally substituted divalent heteroaliphatic group, wherein one or more methylene units of said group are optionally and independently replaced by -C(R') 2 -, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R')-, -C(O)S-, or -C(O)O-;

[0174] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 alicyclic ring, C 6-20 aryl ring, 5 - 20 membered heteroaryl ring having 1 - 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3 - 20 membered heterocyclic group having 1 - 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0175] Each R' is independently -R, -C(O)R, -CO 2 R, or -SO 2 R;

[0176] Each R is independently -H or an optionally substituted group, said optionally substituted group being selected from C 1-30 aliphatic, C having 1 - 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 aryl aliphatic, C having 1 - 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30Aryl heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or

[0177] Two R groups optionally and independently together form a covalent bond, or:

[0178] Two or more R groups on the same atom optionally and independently together with said atom form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring, said monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to said atom; or

[0179] Two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring, said monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms.

[0180] In some embodiments, a1 is 1. In some embodiments, a2 is 1. In some embodiments, b is 1. In some embodiments, the compound of formula I-b has

[0181] In some embodiments, each amino acid residue, such as each Xaa in formula I-b, is independently an amino acid residue having the structure of formula A-I. In some embodiments, each Xaa independently has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -CO-. In some embodiments, two or more side chains of an amino acid residue (e.g., in the compound of formula I-a), such as R a2 or R a3 of one amino acid residue and R a2 or R a3 of another amino acid residue, optionally together form a bridge (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.), for example, in some embodiments, two cysteine residues form an -S-S- bridge, as commonly observed in natural proteins. In some embodiments, the formed bridge has the structure of L b , where L b is L a as described in the present disclosure. In some embodiments, each end of L b is independently connected to the backbone atoms of the cyclic peptide (e.g., by -(Xaa) in formula I-az - the ring atoms of the formed ring). In some embodiments, L b comprises an R group (e.g., when the methylene units of L b are replaced by -C(R) 2 - or -N(R)-), wherein the R group together with the R groups attached to the backbone atoms (e.g., R a1 、R a2 、R a3 etc., in the case of R) and the intervening atoms form a ring. In some embodiments, L b is connected to the ring through the side chain of an amino acid residue (e.g., Xaa in Formula I-a), e.g., a ring formed by -(Xaa) z - in Formula I-b. In some embodiments, such side chains contain an amino group or a carboxylic acid group.

[0182] In some embodiments, R c -(Xaa)z- is an antibody-binding portion (R c -(Xaa)z-H binds to an antibody). In some embodiments, R c -(Xaa)z- is a general antibody-binding portion. In some embodiments, R c -(Xaa)z- is a general antibody-binding portion that can bind to antibodies with different Fab regions. In some embodiments, R c -(Xaa)z- is a general antibody-binding portion that can bind to the Fc region. In some embodiments, the antibody-binding portion (e.g., the general antibody-binding portion having the R c -(Xaa)z- structure) can bind to the Fc region that binds to an Fc receptor. In some embodiments, R c -(Xaa)z- has

[0183] In certain embodiments, the compound (e.g., a medicament, an ARM, etc.) has Formula III:

[0185] or a pharmaceutically acceptable salt thereof, wherein:

[0186] Each R 7 is independently hydrogen or an optionally substituted group, and the optionally substituted group is selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0187] R 7 The R group and the R groups attached to the same carbon atom 7’ optionally together with the intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocycle or a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0188] Each R7' is independently hydrogen or optionally substituted C1-3 aliphatic;

[0189] Each R8 is independently hydrogen or optionally substituted C1-4 aliphatic, or:

[0190] R 8 The group and its adjacent R 7 optionally together with the intervening atoms form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0191] R 9 is hydrogen, optionally substituted C 1-3 aliphatic or -C(O)-(optionally substituted C 1-3 aliphatic);

[0192] L3 is a linker

[0193] TBT is a target binding moiety; and

[0194] o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0195] 2. Definitions:

[0196] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version) and the Handbook of Chemistry and Physics (75th edition). In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0197] Administration: As used herein, the term "administer" generally refers to the administration of a composition to a subject or system. One of ordinary skill in the art will appreciate that, where appropriate, a variety of routes may be used to administer to a subject (e.g., a human). For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or include, for example, one or more of topical administration to the dermis, intradermal, inter-dermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a particular organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may involve intermittent (e.g., multiple doses separated in time) dosing and / or periodic (e.g., single doses separated by a common time period) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected time period.

[0198] Agent: Generally speaking, as used herein, the term "agent" can be used to refer to a compound or entity of any chemical class, including, for example, polypeptides, nucleic acids, saccharides, lipids, small molecules, metals, or combinations or complexes thereof. In appropriate cases, as will be clear to those skilled in the art from the context, the term can be used to refer to an entity that is or contains a cell or organism or a fraction, extract, or component thereof. Alternatively or additionally, as is clear from the context, the term can be used to refer to a natural product as it is found in nature and / or obtained from nature. In some examples, again as will be clear from the context, the term can be used to refer to one or more artificial entities as it is produced by human manipulation and / or not found in nature. In some embodiments, the agent can be used in isolated or pure form; in some embodiments, the agent can be used in crude form. In some embodiments, potential agents can be provided as a collection or library, for example, the collection or library can be screened to identify or characterize the active agents therein. In some cases, the term "agent" can refer to a compound or entity that is or contains a polymer; in some cases, the term can refer to a compound or entity that contains one or more polymer moieties. In some embodiments, the term "agent" can refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or one or more specific polymer moieties. In some embodiments, the term can refer to a compound or entity that lacks or is substantially free of any polymer moiety. In some embodiments, the agent is a compound. In some embodiments, the agent is an ARM as described herein.

[0199] Aliphatic: As used herein, "aliphatic" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or contains one or more unsaturated units, or a combination thereof. Unless otherwise specified, aliphatic groups contain 1-100 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, and alkynyl groups and hybrids thereof.

[0200] Alkenyl: As used herein, the term "alkenyl" refers to an aliphatic group as defined herein having one or more double bonds.

[0201] Alkenylene: The term "alkenylene" refers to a divalent alkenyl group.

[0202] Alkyl: As used herein, the term "alkyl" is given its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In some embodiments, the alkyl has 1-100 carbon atoms. In certain embodiments, the straight-chain or branched-chain alkyl has about 1-20 carbon atoms in its backbone (e.g., for straight-chain, C 1 -C 20 ; for branched-chain, C 2 -C 20 ), and alternatively has about 1-10 carbon atoms. In some embodiments, the cycloalkyl ring has about 3-10 carbon atoms in its ring structure (where such rings are monocyclic, bicyclic, or polycyclic), and alternatively has about 5, 6, or 7 carbons in the ring structure. In some embodiments, the alkyl group can be a lower alkyl group, where the lower alkyl group contains 1-4 carbon atoms (e.g., for straight-chain lower alkyl, C 1 -C 4 ).

[0203] Alkylene: The term "alkylene" refers to a divalent alkyl group.

[0204] Amino acid: In its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain (e.g., by forming one or more peptide bonds). In some embodiments, the amino acid contains an amino group and a carboxylic acid group. In some embodiments, the amino acid has the general structure NH(R’)-C(R’) 2 -COOH, where each R' is independently as described in the present disclosure. In some embodiments, the amino acid has the general structure H 2 N-C(R’) 2 -COOH, where R' is as described in the present disclosure. In some embodiments, the amino acid has the general structure H 2N-C(H)(R’)-COOH, wherein R' is as described in the present disclosure. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a non-natural amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. A "standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, whether prepared synthetically or obtained from natural sources. In some embodiments, compared to the above general structure, the amino acids in the polypeptide that include the carboxyl and / or amino-terminal amino acids may contain structural modifications. For example, in some embodiments, compared to the general structure, the amino acid may be modified by methylation, amidation, acetylation, polyethylene glycolylation, glycosylation, phosphorylation, and / or substitution (e.g., substitution of an amino group, a carboxylic acid group, one or more protons, one or more hydrogens, and / or a hydroxyl group). In some embodiments, such modifications may, for example, alter the circulating half-life of the polypeptide containing the modified amino acid compared to a polypeptide containing unmodified amino acids that are otherwise identical. In some embodiments, such modifications do not significantly alter the relevant activity of the polypeptide containing the modified amino acid compared to a polypeptide containing unmodified amino acids that are otherwise identical. As will be clear from the context, in some embodiments, the term "amino acid" may be used to refer to a free amino acid; in some embodiments, it may be used to refer to an amino acid residue of a polypeptide.

[0205] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human of either sex at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, the animal can be a transgenic animal, a genetically engineered animal, and / or a clone.

[0206] Antibody: As used herein, the term “antibody” refers to a polypeptide that comprises standard immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, a naturally-occurring intact antibody is a ~150 kD tetrameric agent composed of two identical heavy chain polypeptides (each ~50 kD) and two identical light chain polypeptides (each ~25 kD), which heavy and light chain polypeptides associate with one another to form the structure commonly referred to as the “Y-shaped” structure. Each heavy chain contains at least four domains (each domain being approximately 110 amino acids in length) - an amino-terminal variable (VH) domain (at the tip of the Y structure), followed by three constant domains: CH1, CH2, and carboxy-terminal CH3 (at the base of the Y stem). A short region called the “switch” joins the heavy chain variable region to the constant region. The “hinge” joins the CH2 and CH3 domains to the remainder of the antibody. Two disulfide bonds in the hinge region join the two heavy chain polypeptides in the intact antibody to one another. Each light chain contains two domains - an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. The intact antibody tetramer contains two heavy chain-light chain dimers, where the heavy and light chains are joined to one another by a disulfide bond; two additional disulfide bonds join the heavy chain hinge regions to one another, thereby joining the dimers to one another and forming the tetramer. Naturally-occurring antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized as an “immunoglobulin fold”, which is formed by two β-sheets (e.g., 3-strand, 4-strand, or 5-strand sheets) packing against one another in a compact, antiparallel β-barrel. Each variable domain contains three hypervariable loops, called “complementary determining regions” (CDR1, CDR2, and CDR3), and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When a natural antibody folds, the FR regions form β-sheets that provide a structural framework for the domain, and the CDR loop regions from the heavy and light chains come together in three-dimensional space, thereby creating a single hypervariable antigen-binding site at the tip of the Y structure. The Fc region of a naturally-occurring antibody binds elements of the complement system and also binds receptors on effector cells (including, for example, effector cells that mediate cytotoxicity). As is known in the art, the affinity of the Fc region for Fc receptors and / or other binding properties can be modulated by glycosylation or other modifications. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure comprise a glycosylated Fc domain, including such glycosylated Fc domains having modified or engineered glycosylation. For the purposes of the present disclosure, in certain embodiments, any polypeptide or polypeptide complex that contains sufficient immunoglobulin domain sequences found in a natural antibody may be referred to as and / or used as an “antibody”, whether such polypeptide is naturally-occurring (e.g., produced by an organism in response to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods.In some embodiments, the antibody is a polyclonal antibody; in some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody has a constant region sequence characteristic of a murine, rabbit, primate, or human antibody. In some embodiments, the antibody sequence elements are humanized, primatized, chimerized, etc., as known in the art. In addition, as used herein, the term "antibody" in the appropriate embodiments (unless otherwise specified or clear from the context) may refer to any construct or form known or developed in the art for exploiting antibody structural and functional features in alternative presentations. For example, in some embodiments, the antibodies used in accordance with the present disclosure are in a form selected from, but not limited to: intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g.,

[0207] About: As used herein, when applied to one or more values of interest, the term "about" or "approximately" refers to a value similar to the reference value. In certain embodiments, the term "about" or "approximately" refers to a range of values falling within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the reference value, unless otherwise specified or otherwise obvious from the context (unless such numbers exceed 100% of the possible value).

[0208] Aryl: The term "aryl", used alone or as part of a larger moiety (such as in "aralkyl", "aralkoxy", "aryloxyalkyl", etc.), refers to a monocyclic, bicyclic, or polycyclic ring system having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, the aryl group is a monocyclic, bicyclic, or polycyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, the aryl group is a biaryl group. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracenyl, etc., which may have one or more substituents. In some embodiments, also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc., wherein the attached group or point is on the aryl ring.

[0209] Association: As used herein, two events or entities are "associated" with each other if the presence, level, and / or form of one event or entity is related to the presence, level, and / or form of another event or entity. For example, if the presence, level, and / or form of a particular entity is related to the incidence and / or susceptibility of a disease, disorder, or condition (e.g., in a relevant population), then the particular entity (e.g., a nucleic acid (e.g., genomic DNA, transcript, mRNA, etc.), polypeptide, genetic trait, metabolite, microorganism, cell, etc.) is considered to be associated with the particular disease, disorder, or condition.

[0210] Vehicle: As used herein, refers to a diluent, adjuvant, excipient, or medium with which a composition is administered. In some exemplary embodiments, the vehicle can include a sterile liquid, such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the vehicle is or comprises one or more solid components.

[0211] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, groups of conditions, etc., which may differ from each other but are similar enough to permit comparison between them, such that one of ordinary skill in the art will understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, groups of comparable conditions, environments, individuals, or populations are characterized by a plurality of substantially identical characteristics and one or a small number of different characteristics. One of ordinary skill in the art will understand that, in context, how much identity of two or more such agents, entities, situations, groups of conditions is required to be considered comparable in any given case. For example, one of ordinary skill in the art will understand that groups of environments, individuals, or populations are comparable to each other when characterized by a sufficient number and type of substantially identical characteristics to warrant the reasonable conclusion that differences in results or observed phenomena obtained under different groups of environments, individuals, or populations are caused by or indicative of changes in these altered characteristics.

[0212] Alicyclic: As used herein, the term "alicyclic" refers to a saturated or partially unsaturated aliphatic monocyclic, bicyclic, or polycyclic system having, for example, 3 to 30 members, wherein the aliphatic ring system is optionally substituted. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3 - 6 carbons. The term "alicyclic" may also include aliphatic rings fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, wherein the attached group or point is on the aliphatic ring. In some embodiments, the carbocyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, the carbocyclic group is polycyclic. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C 3 -C 6 -hydrocarbon or a C 8 -C 10 -bicyclic hydrocarbon, or a completely saturated or partially unsaturated C 9 -C 16 -tricyclic hydrocarbon.

[0213] Derivative: As used herein, the term "derivative" refers to a structural analogue of a reference substance. That is, a "derivative" is a substance that shows significant structural similarity to the reference substance, e.g., sharing a core or common structure, but also differing in some means of separation. In some embodiments, a derivative is a substance that can be produced from the reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be produced by a synthetic method that is substantially similar (e.g., sharing multiple steps) to the synthetic method used to produce the reference substance.

[0214] Dosage form or unit dosage form: Those skilled in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dose (or a whole or partial portion thereof) suitable for administration according to a dosing regimen that has been determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., administered with a therapeutic dosing regimen). Those of ordinary skill in the art understand that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0215] Dosing regimen: Those skilled in the art will understand that the term "dosing regimen" can be used to refer to a set of unit doses (usually more than one), which are administered to a subject individually, usually spaced apart by a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may include one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each dose being spaced apart from the other doses in time. In some embodiments, the individual doses are spaced apart by the same length of time period; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses. In some embodiments, all of the doses within the dosing regimen have the same unit dose amount. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, the dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount the same as the first dose amount. In some embodiments, when administered in a relevant population, the dosing regimen is associated with a desired or beneficial outcome (i.e., is a therapeutic dosing regimen).

[0216] Halogen: The term "halogen" means F, Cl, Br, or I.

[0217] Heteroaliphatic: The term "heteroaliphatic" is given its ordinary meaning in the art and refers to an aliphatic group as described herein, wherein one or more carbon atoms are replaced by one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.).

[0218] Heteroaryl: The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety (e.g., "heteroalkyl" or "heteroalkoxy") refer to a monocyclic, bicyclic or polycyclic system having, for example, a total of 5 to 30 (e.g., 5, 6, 9, 10, 14, etc.) ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, the heteroatom is nitrogen, oxygen or sulfur. In some embodiments, the heteroaryl group is a group having 5 to 14 ring atoms (i.e., monocyclic, bicyclic or polycyclic); in some embodiments, it is a group having 5, 6, 9, 10 or 14 ring atoms. In some embodiments, the heteroaryl group has 6, 10 or 14 π electrons shared in a cyclic array; and in addition to carbon atoms, it has one to five heteroatoms. Heteroaryl groups include but are not limited to thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. In some embodiments, heteroaryl is heteroarylene, such as bipyridyl, etc. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl rings, cycloaliphatic rings or heterocyclic rings, wherein the attached group or point is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic or polycyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaryl group", and any of these terms includes a ring optionally substituted. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0219] Heteroatom: The term "heteroatom" means an atom that is neither carbon nor hydrogen. In some embodiments, the heteroatom is oxygen, sulfur, nitrogen, phosphorus, boron or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any basic nitrogen of a heterocycle or the quaternized form of a replaceable nitrogen (e.g., as in N in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +( as in N-substituted pyrrolidinyl); etc.). In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen or sulfur.

[0220] Heterocyclic group: As used herein, the terms "heterocycle", "heterocyclic group", "heterocyclic moiety", and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic moiety (e.g., 3 - 30 membered) having one or more heteroatoms as ring atoms. In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, the heterocyclic group is a saturated or partially unsaturated stable 3 - to 7 - membered monocyclic or 7 - to 10 - membered bicyclic heterocyclic moiety having one or more (preferably one to four) heteroatoms as defined above in addition to carbon atoms. When used in reference to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 - 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4 - dihydro - 2H - pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N - substituted pyrrolidinyl). The heterocycle can be attached to its side groups at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolyl, diaza

[0221] "Improve", "increase", or "decrease": As used herein, these terms or grammatically comparable comparative terms denote a value relative to a comparable reference measurement. For example, in some embodiments, the evaluation value obtained with a target agent can be "improved" relative to the evaluation value obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, the evaluation value obtained in a target subject or system can be "improved" relative to the evaluation value obtained in the same subject or system under different conditions (e.g., before or after an event such as the administration of the target agent) or in different comparable subjects (e.g., in a comparable subject or system different from the target subject or system, in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or before exposure to the condition or agent, etc.). In some embodiments, the comparative term refers to a statistically relevant difference (e.g., having a prevalence and / or magnitude sufficient to achieve statistical relevance). One of ordinary skill in the art will know or be able to readily determine in a given context the degree and / or prevalence of the difference (which is required or sufficient to achieve such statistical significance).

[0222] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a moiety that contains at least one double bond or triple bond. The term "partially unsaturated" is intended to encompass groups having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0223] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent (e.g., a compound) formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage amount suitable for administration in a treatment regimen, which unit dosage amount, when administered to a relevant population, exhibits a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for: oral administration, e.g., drench (aqueous or non-aqueous solution or suspension), tablets (e.g., those directed for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or a sustained release formulation; topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, lung, or oral cavity; intravaginal or rectal, e.g., as a vaginal suppository, cream, or foam; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0224] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and that have a reasonable benefit / risk ratio commensurate therewith.

[0225] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, which participates in the delivery or transport of the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffering solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0226] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of a compound that are suitable for use in a pharmaceutical context, i.e., salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts formed by the reaction of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other known methods (such as ion exchange). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic base addition salts, such as salts formed by the reaction of an acidic group of the provided compound with a base. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. In some embodiments, pharmaceutically acceptable salts are ammonium salts (e.g., -N(R) 3 + ). In some embodiments, pharmaceutically acceptable salts are sodium salts. In some embodiments, pharmaceutically acceptable salts are calcium salts. In some embodiments, pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium cations, quaternary ammonium cations, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates. In some embodiments, the provided compound is in the form of a pharmaceutically acceptable salt.

[0227] Protecting Group: As used herein, the phrase "protecting group" (or "protection group") refers to a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformation. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. A "Si protecting group" is a protecting group that contains a Si atom, such as Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, tert-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., tert-butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl). Generally, the Si protecting group is attached to an oxygen atom. A review of the field of protecting group chemistry is available (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Such protecting groups (and the related protected moieties) are described in detail below.

[0228] The protected hydroxy groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. Examples of suitably protected hydroxy groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, propionates, valerates, crotonates, and benzoates. Specific examples of suitable esters include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxovalerates, 4,4-(ethylenedithio)valerates, pivalates (trimethylacetates), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoates, 2,4,6-trimethylbenzoates. Examples of suitable carbonates include 9-fluorenylmethyl carbonates, ethyl carbonates, 2,2,2-trichloroethyl carbonates, 2-(trimethylsilyl)ethyl carbonates, 2-(phenylsulfonyl)ethyl carbonates, vinyl carbonates, allyl carbonates, and p-nitrobenzyl carbonates. Examples of suitable silyl ethers include trimethylsilyl ethers, triethylsilyl ethers, tert-butyldimethylsilyl ethers, tert-butyldiphenylsilyl ethers, triisopropylsilyl ethers, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl ethers, benzyl ethers, p-methoxybenzyl ethers, 3,4-dimethoxybenzyl ethers, trityl ethers, tert-butyl ethers, and allyl ethers, or derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl ethers, methylthiomethyl ethers, (2-methoxyethoxy)methyl ethers, benzyloxymethyl ethers, β-(trimethylsilyl)ethoxymethyl ethers, and tetrahydropyran-2-yl ethers. Examples of suitable arylalkyl ethers include benzyl ethers, p-methoxybenzyl (MPM) ethers, 3,4-dimethoxybenzyl ethers, o-nitrobenzyl ethers, p-nitrobenzyl ethers, p-halobenzyl ethers, 2,6-dichlorobenzyl ethers, p-cyanobenzyl ethers, 2-pyridylmethyl ethers, and 4-pyridylmethyl ethers.

[0229] Protected amines are well known in the art and include those described in detail in Greene (1999). Suitable mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allylamines, amides, etc. Examples of suitable mono-protected amino moieties include tert-butoxycarbonylamino (-NHBOC), ethoxycarbonylamino, methoxycarbonylamino, trichloroethoxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxycarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethoxycarbonylamino (-NHFmoc), formamido, acetamido, chloroacetamido, dichloroacetamido, trichloroacetamido, phenylethanamido, trifluoroacetamido, benzamido, tert-butyldiphenylsilyl, etc. Suitable di-protected amines include amines substituted with two substituents (independently selected from those described above as mono-protected amines), and further include cyclic imides such as phthalimide, maleimide, succinimide, etc. Suitable di-protected amines also include pyrrole, 2,2,5,5-tetramethyl-[1,2,5]azadithiolane, and azides, etc.

[0230] Protected aldehydes are well known in the art and include those described in detail in Greene (1999). Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, etc. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazone and its derivatives.

[0231] Protected carboxylic acids are well known in the art and include those described in detail in Greene (1999). Suitable protected carboxylic acids further include, but are not limited to, optionally substituted C 1-6 aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, etc. Examples of such ester groups include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, benzyl ester and phenyl ester, where each group is optionally substituted. Other suitable protected carboxylic acids include oxazolines and orthoesters.

[0232] Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates and thiocarbamates, etc. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl thioethers and substituted benzyl thioethers, triphenylmethyl thioether and trichloroethoxycarbonyl thioester, to name just a few.

[0233] Reference: As used herein, a standard or control to which a comparison is made. For example, in some embodiments, a test agent, animal, individual, population, sample, sequence, or value is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially contemporaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as understood by one of ordinary skill in the art, the reference or control is determined or characterized under conditions or circumstances comparable to those being evaluated. One of ordinary skill in the art will understand that reliance on and / or comparison to a particular potential reference or control is justified only when there is sufficient similarity.

[0234] Substituted: As described herein, the compounds of the present disclosure may contain optionally substituted / substituted moieties. Generally, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the designated group, the substituents at each position may be the same or different. The combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to compounds that do not substantially change when subjected to the conditions tolerated during their production, testing, and in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0235] Suitable monovalent substituents include halogen; -(CH 2 ) 0-4 R o ; -(CH 2 ) 0-4 OR o ; -O(CH 2 ) 0-4 R o ; -O-(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 CH(OR o ) 2 ; -(CH o ) 2 ) 0-4 Ph; -(CH o ) 2 ) 0-4 O(CH 2 )0-1 Ph; -CH=CHPh which may be substituted by R o ; -(CH o ) 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R o ) 2 ; -(CH 2 ) 0-4 N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH 2 ) 0-4 N(R o )C(O)N(R o ) 2 ; -N(R o )C(S)N(R o ) 2 ; -(CH 2 ) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)N(R o ) 2 ; -N(R o )N(R o )C(O)OR o ; -(CH 2 ) 0-4 C(O)R o ; -C(S)R o ; -(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 C(O)SR o ; -(CH 2 ) 0-4 C(O)OSi(R o ) 3 ; -(CH 2 ) 0-4 OC(O)Ro ; -OC(O)(CH 2 ) 0-4 SR o ; -(CH 2 ) 0-4 SC(O)R o ; -(CH 2 ) 0-4 C(O)N(R o ) 2 ; -C(S)N(R o ) 2 ; -C(S)SR o ; -SC(S)SR o ; -(CH 2 ) 0-4 OC(O)N(R o ) 2 ; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH 2 C(O)R o ; -C(NOR o )R o ; -(CH 2 ) 0-4 SSR o ; -(CH 2 ) 0-4 S(O) 2 R o ; -(CH 2 ) 0-4 S(O) 2 OR o ; -(CH 2 ) 0-4 OS(O) 2 R o ; -S(O) 2 N(R o ) 2 ; -(CH 2 ) 0-4 S(O)R o ; -N(R o )S(O) 2 N(R o ) 2 ; -N(R o )S(O) 2 R o ; -N(OR o )R o ; -C(NH)N(R o ) 2 ; -Si(Ro ) 3 ;-OSi(R o ) 3 ;-OSi(OR o ) 3 ;-P(R o ) 2 ;-P(OR o ) 2 ;-OP(R o ) 2 ;-OP(OR o ) 2 ;-N(R o )P(R o ) 2 ;-OP(O)(R o ) 2 ;-OP(O)(OR o ) 2 ;-N(R o )P(O)(R o ) 2 ;-N(R o )P(O)(OR o ) 2 ;-B(R o ) 2 ;-OB(R o ) 2 ;-OB(OR o ) 2 ;-P(O)(R o ) 2 ;-OP(O)(R o ) 2 ;-(C 1-4 linear or branched alkylene)O-N(R o ) 2 ;or -(C 1-4 linear or branched alkylene)C(O)O-N(R o ) 2 ;wherein each R o may be substituted as defined hereinafter and is independently hydrogen, C 1-20 aliphatic, C 1-20 heteroaliphatic having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, -CH 2 -(C 6-14 aryl), -O(CH 2 ) 0-1 (C 6-14 aryl), -CH 2-(5-14 membered heteroaryl ring), a 5-20 membered monocyclic, bicyclic or polycyclic saturated ring, partially unsaturated ring or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the above definition, two independently occurring o together with one or more intervening atoms form a 3-20 membered monocyclic, bicyclic or polycyclic saturated ring, partially unsaturated ring or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined hereinafter.

[0236] R o (or by joining two independently occurring R o together with their intervening atoms to form a ring) suitable monovalent substituents on are independently hydrogen, -(CH 2 ) 0-2 R λ 、-(haloR λ ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR λ 、-(CH 2 ) 0-2 CH(OR λ ) 2 、-O(haloR λ ), -CN, -N 3 、-(CH 2 ) 0-2 C(O)R λ 、-(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR λ 、-(CH 2 ) 0-2 SR λ 、-(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 、-(CH 2 ) 0-2 NHR λ 、-(CH 2 ) 0-2 NR λ 2 、-NO 2 、-SiR λ 3 、-OSiR λ 3 、-C(O)SRλ , -(C 1-4 linear or branched alkylene)C(O)OR λ , or -SSR λ , wherein each R λ is unsubstituted or is substituted only by one or more halogens preceded by "halo-" and is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph and a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Suitable divalent substituents on the saturated carbon atoms of R o include =O and =S.

[0237] Suitable divalent substituents (e.g., on suitable carbon atoms, nitrogen atoms, etc.) independently include the following: =O, =S, =CR * 2 , =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O-, or -S(C(R * 2 )) 2-3 S-, wherein each R * may be substituted as defined below and is independently hydrogen, C 1-20 aliphatic, C 1-20 heteroaliphatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, -CH 2 -(C 6-20 aryl), -O(CH 2 ) 0-1 (C 6-20 aryl), -CH 2 -(a 5- to 20-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus), a 5- to 20-membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the above definition, two independently occurring R *Together with one or more intervening atoms, form a 3- to 20-membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined hereinafter. Suitable divalent substituents bonded to an ortho-substitutable atom of an "optionally substituted" group include: -O(CR * 2 ) 2-3 O-.

[0238] R * (or, by joining two independently occurring R * together with their intervening atoms, form a ring), suitable monovalent substituents on R 2 ) 0-2 R λ are independently hydrogen, -(CH λ ) 2 R 0-2 OH, -(CH 2 ) 0-2 OR λ 、-(CH 2 ) 0-2 CH(OR λ ) 2 、-O(haloR λ )、-CN、-N 3 、-(CH 2 ) 0-2 C(O)R λ 、-(CH 2 ) 0-2 C(O)OH、-(CH 2 ) 0-2 C(O)OR λ 、-(CH 2 ) 0-2 SR λ 、-(CH 2 ) 0-2 SH、-(CH 2 ) 0-2 NH 2 、-(CH 2 ) 0-2 NHR λ 、-(CH 2 ) 0-2 NR λ 2 、-NO 2 、-SiR λ 3 、-OSiR λ 3 、-C(O)SR λ 、-(C1-4 (a linear or branched alkylene)C(O)OR λ 、 or -SSR λ wherein each R λ is unsubstituted or is substituted only by one or more halogens, preceded by "halo-", and is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph and a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents of R * include =O and =S.

[0239] In some embodiments, suitable substituents on a replaceable nitrogen of an "optionally substituted" group include

[0240] In some embodiments,

[0241] Subject: As used herein, the term "subject" or "test subject" refers to any organism to which the provided compounds or compositions are administered according to the present disclosure, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms, etc.) and plants. In some embodiments, the subject may have a disease, disorder, and / or condition, and / or be susceptible to a disease, disorder, and / or condition. In some embodiments, the subject is human.

[0242] Susceptible: An individual susceptible to a disease, disorder, and / or condition is an individual at higher risk of developing the disease, disorder, and / or condition than a member of the general public. In some embodiments, an individual susceptible to a disease, disorder, and / or condition may not be diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0243] Therapeutic agent: As used herein, the phrase "therapeutic agent" refers to an agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological action when administered to a subject. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, improve, relieve, inhibit, prevent one or more symptoms or characteristics of a disease, disorder, and / or condition, delay its onset, reduce its severity, and / or reduce its incidence. In some embodiments, the provided compounds can be used as therapeutic agents.

[0244] Treatment regimen: The term "treatment regimen" as used herein refers to a dosing regimen, the administration of which in a relevant population may be associated with a desired or beneficial therapeutic outcome.

[0245] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" means the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent a disease, disorder, and / or condition and / or delay its onset when administered to a subject having or susceptible to the disease, disorder, and / or condition. As will be understood by one of ordinary skill in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, improves, relieves, inhibits, prevents one or more symptoms or characteristics of the disease, disorder, and / or condition, delays its onset, reduces its severity, and / or reduces its incidence. In some embodiments, a therapeutically effective amount is administered as a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount. In some embodiments, the provided compounds are administered in a therapeutically effective amount, as a single dose or multiple unit doses.

[0246] Treat: As used herein, the term "treat (treat, treatment or treating)" refers to any method used to partially or completely alleviate, improve, relieve, inhibit, prevent one or more symptoms or characteristics of a disease, disorder, and / or condition, delay its onset, reduce its severity, and / or reduce its incidence. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment can be administered to a subject who exhibits only early signs of a disease, disorder, and / or condition, for example, for the purpose of reducing the risk of developing a pathology associated with the disease, disorder, and / or condition.

[0247] Unit dose: As used herein, the expression "unit dose" refers to an amount administered as a single dose and / or as a physically discrete unit of a pharmaceutical composition. In many embodiments, the unit dose contains a predetermined amount of the active agent. In some embodiments, the unit dose contains the entire single dose of the medicament. In some embodiments, more than one unit dose is administered to achieve the total single dose. In some embodiments, it is necessary or expected that multiple unit doses be administered to achieve the desired effect. The unit dose can be, for example, a volume of a liquid (e.g., an acceptable carrier) that contains a predetermined amount of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation, or a drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It should be understood that the unit dose can be present in a formulation that contains any of a variety of components other than the one or more therapeutic agents. For example, it can include an acceptable carrier (e.g., a pharmaceutically acceptable carrier), diluent, stabilizer, buffer, preservative, etc., as described below. Those skilled in the art will understand that in many embodiments, the total appropriate daily dose of a particular therapeutic agent can include a fraction or multiple unit doses, and it can be determined, for example, by the attending physician within the scope of reasonable medical judgment. In some embodiments, the specific effective dose level for any particular subject or organism can depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific active compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration and the excretion rate of the specific active compound employed; the duration of the treatment; drugs and / or additional therapies used in combination with or concurrently with one or more specific compounds employed, and similar factors well known in the medical arts.

[0248] Unsaturated: As used herein, the term "unsaturated" means that the moiety has one or more unsaturated units.

[0249] Wild type: As used herein, the term "wild type" has the meaning understood in the art and refers to an entity having a structure and / or activity as found in nature in a "normal" (as compared to mutant, diseased, altered, etc.) state or environment. Those of ordinary skill in the art will understand that wild type genes and polypeptides generally exist in a variety of different forms (e.g., alleles).

[0250] Unless otherwise indicated, salts (such as pharmaceutically acceptable acid or base addition salts), stereoisomeric forms, and tautomeric forms of the provided compounds (e.g., medicaments, ARMs, etc.) are included. Unless otherwise indicated, the structures depicted herein also include those containing various isotopes (e.g., hydrogen replaced by deuterium or tritium, carbon replaced by 13 C or 14Compounds that are C-substituted, etc. In some embodiments, the composition comprising the compound comprises an isotope at an enriched level in the compound. Among other things, such compounds and compositions can be used as analytical tools, probes in biological assays, therapeutic agents, etc.

[0251] Unless otherwise clearly apparent from the context, in this disclosure text: (i) the term "a" can be understood to mean "at least one"; (ii) the term "or" can be understood to mean "and / or"; (iii) the terms "comprising" and "including" can be understood to cover the components or steps listed item by item, whether presented alone or in combination with one or more additional components or steps; (iv) the terms "about" and "approximately" can be understood to allow for the standard variations known to those of ordinary skill in the art; (v) where ranges are provided, endpoints are included.

[0252] 3. Cellular immunotherapy

[0253] A variety of immune cells, particularly NK cells, can be used in conjunction with the agents described herein to treat a variety of conditions, disorders, or diseases, including cancer. Such cells can be administered before, simultaneously with, and / or after the agents described herein (e.g., ARM). In some embodiments, such cells (e.g., NK cells) are administered simultaneously with the agent (e.g., ARM) in the same composition comprising both NK cells and ARM. In some embodiments, such cells (e.g., NK cells) are administered simultaneously with the agent (e.g., ARM) in separate compositions (e.g., a composition comprising NK cells but not ARM and a composition comprising ARM but not NK cells).

[0254] As will be understood by those skilled in the art, useful immune cells such as NK cells can be derived from various sources and / or engineered by a variety of methods. For example, in some embodiments, NK cells are derived from stem cells. In some embodiments, NK cells are derived from an iPSC line. In some embodiments, NK cells are derived from a clonal master iPSC line. In some embodiments, NK cells are engineered to express certain receptors, e.g., a high-affinity, optionally non-cleavable CD16 receptor. In some embodiments, NK cells are engineered to express a chimeric antigen receptor (CAR), e.g., in some embodiments, NK cells can be engineered to express an anti-CD19 CAR. In some embodiments, NK cells are CAR-NK cells. In some embodiments, NK cells are engineered to express a cytokine receptor. In some embodiments, NK cells comprise an IL-15 receptor fusion that enhances persistence and expansion capacity without the need for co-administration of cytokine support. In some embodiments, NK cells are engineered to block the expression of certain cellular proteins (e.g., certain cell surface proteins). In some embodiments, NK cells are engineered to block the expression of CD38. In some embodiments, NK cells are derived from the placenta. In some embodiments, NK cells are donor NK cells. In some embodiments, NK cells are haploidentical donor NK cells. In some embodiments, NK cells are mismatched donor NK cells. In some embodiments, NK cells are related donor NK cells, e.g., mismatched related donor NK cells. In some embodiments, NK cells are unrelated donor NK cells. In some embodiments, NK cells are derived from a subject, e.g., a patient. In some embodiments, the techniques provided include innate cell conjugates, e.g., innate cell conjugates that bind to innate cells (e.g., NK cells and macrophages) while binding to specific tumor cells. In some embodiments, NK cells are derived from umbilical cord blood stem cells and progenitors. In some embodiments, NK cells are obtained by modulation of signaling pathways (e.g., the Notch signaling pathway). In some embodiments, nanoparticles are used to improve and / or maintain the growth of NK cells. In some embodiments, as described herein, NK cells are generated ex vivo. In some embodiments, NK cells can be cryopreserved and stored in multiple doses as an off-the-shelf cell therapy.Examples of some such technologies include those used by companies such as Fate Therapeutics, NantKwest Inc., Celularity, Inc., GC Pharma, Sorrento Therapeutics, Inc., Affimed GmbH / MD Anderson Cancer Center, Gamida Cell Ltd., Nohla Therapeutics, Kiadis Pharma N.V., etc. Those skilled in the art will understand that in the technologies provided that include the ARMs described herein, antibodies and / or CARs specific for certain antigens used in some such technologies may not be required and they can be used optionally.

[0255] Cell population / preparation

[0256] In some embodiments, the useful cells (e.g., NK cells) are processed before being administered to a subject. In many embodiments, NK cells are enriched, pre-activated, and / or expanded in vitro before being administered to a subject. In some embodiments, the composition comprising NK cells for administration is enriched in NK cells compared to a reference composition (e.g., blood from the subject to whom such a composition is to be administered). In some embodiments, the enrichment is or comprises an increase in the number of cells per unit volume (e.g., per mL). In some embodiments, the enrichment is or comprises an increase in the percentage of NK cells in such a composition. In some embodiments, the enrichment is or comprises an increase in the number of cells per unit volume and an increase in the percentage of NK cells in the composition. In some embodiments, the composition is a substantially pure NK cell composition because the non-NK cells in the composition are "impurities" from the production process (e.g., due to incomplete separation, purification, etc.). As those skilled in the art will understand, chemical and biological processes rarely (if ever) complete and / or proceed to completion or achieve or avoid absolute results. Thus, the term "substantially" is used in the present disclosure to obtain the inherent integrity that is potentially lacking in many biological and chemical phenomena.

[0257] A variety of techniques for enriching NK cells are available in the art and can be used in accordance with the present disclosure. For example, in some embodiments, NK cells are isolated by leukapheresis, optionally accompanied by purification steps such as CD3 depletion and / or CD56 positive selection. In some embodiments, NK cells (e.g., pre-activated memory-like NK cells) are enriched in CD56 and depleted of CD3-expressing cells compared to a reference NK cell population (e.g., NK cells in donor or subject blood).

[0258] Prior to administration to a subject, NK cells are typically pre-activated, for example, with cytokines (e.g., IL-12, IL-15, and IL-18) for a suitable period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 or more hours, e.g., about 16 hours). In some embodiments, NK cells are treated with cytokines prior to administration. In some embodiments, NK cells are treated with a suitable amount of IL-12 (e.g., about 10 ng / mL), IL-15 (e.g., 50 ng / mL), and IL-18 (e.g., 50 ng / mL) for a suitable period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 or more hours, e.g., about 16 hours) to pre-activate them. The pre-activation conditions of NK cells and the pre-activated NK cells can be evaluated by assessing one or more markers (e.g., CD94, NKG2A, NKp46, CD25, NKp30, NKp44, CD62L, CD27, TRAIL, cytotoxic molecules perforin and granzyme B, etc.). Certain useful markers are described in the following references: Romee et al., Blood 120, 4751-4760, (2012); Leong et al., Biol. Blood Marrow Transplant. 20, 463-473 (2014); Romee et al., Sci Transl Med. September 21, 2016; 8(357):357ra123. doi:10.1126 / scitranslmed.aaf2341; etc. In some embodiments, the NK cells are primary human NK cells that are differentiated into memory-like NK cells in vitro via pre-activation with IL-12, IL-15, and IL-18.

[0259] Among other things, such cytokine-induced memory-like NK cells exhibit enhanced responsiveness to cytokine or activating receptor restimulation for weeks to months after pre-activation and can be particularly useful for treating a variety of conditions, disorders, or diseases including cancer. In some embodiments, such pre-activated memory-like NK cells have enhanced interferon-gamma (IFN-γ) production and / or cytotoxicity against target cells (e.g., cancer cells). Exemplary procedures for preparing, evaluating, and administering such NK cells can be found in: Romee et al., Blood 120, 4751-4760, (2012); Leong et al., Biol. Blood Marrow Transplant. 20, 463-473 (2014); Romee et al., Sci Transl Med. September 21, 2016; 8(357):357ra123.doi:10.1126 / scitranslmed.aaf2341; and the like. In some embodiments, compared to comparable reference NK cells (e.g., NK cells prepared similarly but not pre-activated (e.g., not treated with cytokines, treated only with low-dose IL-15, etc.)), such NK cells have enhanced proliferation, express or express higher levels of high-affinity IL-2 receptor αβγ, and / or provide increased IFN-γ production upon restimulation (e.g., with cytokines or via activating receptors, etc.).

[0260] Compared to reference NK cells, pre-activated memory-like NK cells may have significant differences in the expression of many proteins (e.g., CD94, NKG2A, NKp46, CD25, NKp30, NKp44, CD62L, CD27, TRAIL, cytotoxic molecules perforin and granzyme B, etc.). In some embodiments, such NK cells exhibit a decrease in NKp80 expression. Among other things, such markers can be used to enrich, purify, and / or identify memory-like NK cells, either alone or in combination. Exemplary useful markers can be identified using a variety of techniques, e.g., bulk cell counting and multi-dimensional analysis. Exemplary procedures for identifying proteins that can distinguish pre-activated memory-like NK cells from reference (e.g., control) NK cells and exemplary such proteins are described in Romee et al., Sci Transl Med. September 21, 2016; 8(357):357ra123.doi:10.1126 / scitranslmed.aaf2341.

[0261] In some embodiments, immune cells (e.g., NK cells) are contacted with a GSK3α / β inhibitor. In some embodiments, such cells are pre-activated with a GSK3α / β inhibitor.

[0262] In some embodiments, the immune cells are cytokine-induced memory-like NK cells. In some embodiments, the immune cells are NK cells pre-activated with IL-12, IL-15, and IL-18. In some embodiments, the immune cells are allogeneic, HLA-haploidentical, IL-12, IL-15, and IL-18 pre-activated NK cells. The present invention is not limited thereto, and memory-like NK cells after pre-activation with IL-12, IL-15, and IL-18 may be generated by including a process of differentiation, which results in an alteration of long-term functional capacity. Memory-like NK cells having such functional capacity can be prepared by treatment with other agents (e.g., other cytokines, or other small molecules, peptides, proteins, etc.). Techniques for evaluating treatments such as agents and / or resultant NK cells (e.g., protein markers, assays, etc.) are available in the art and can be used in accordance with the present disclosure (e.g., those described in Romee et al., Sci Transl Med. September 21, 2016; 8(357):357ra123. doi:10.1126 / scitranslmed.aaf2341). In some embodiments, memory-like NK cells have increased expression of inhibitory receptors, activating receptors, and cytokine receptors (e.g., CD94 / NKG2A, NKp30, NKp44, NKp46, NKG2D, CD62L, and CD25, etc.), and / or decreased expression of certain proteins (e.g., NKp80). In some embodiments, the levels of certain receptors remain substantially unchanged (e.g., KIR, CD57, NKG2C, DNAM-1, CD137, CD11b, etc.). In some embodiments, the changes in activating, inhibitory, cytokine, and adhesion receptors are consistent with differentiation. In some embodiments, pre-activation with cytokines provides epigenetic regulation of certain genes (e.g., IFN-γ). For example, in some embodiments, activation with IL-12, IL-15, and IL-18 (e.g., for 5 days) results in decreased methylation of the IFN-γ conserved non-coding sequence 1 locus in human NK cells. In some embodiments, certain pre-activated NK cells (e.g., cytokine-induced cells) exist in an enhanced activation state without substantial differentiation.

[0263] In some embodiments, the NK cells are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or 4, 5, 6, 7, 8, 9, 10, 11 months or several months after pre-activation.

[0264] Among other things, the present disclosure includes the recognition that such NK cells with enhanced properties and / or activities can provide enhanced cancer cell inhibition or killing, which may result in more and / or more severe side effects and / or toxicities, such as off-target toxicity to normal cells. Thus, in some embodiments, the present disclosure provides techniques for reducing such side effects and / or toxicities, which include administering one or more agents (especially ARM), which can in particular promote, encourage, and / or enhance the interaction of NK cells with their targets and reduce the side effects and / or toxicities associated with NK cell administration.

[0265] In some embodiments, NK cells are expanded, for example, before, during, and / or after pre-activation. In some embodiments, NK cells are purified before administration to remove, for example, certain culture media (or their components), activating cytokines, etc.

[0266] In some embodiments, the NK cells to be administered to a subject are isolated and / or expanded from the subject (autologous). In some embodiments, the NK cells to be administered to a subject are isolated and / or expanded from another subject (allogeneic; e.g., from an HLA-haploidentical donor).

[0267] In some embodiments, NK cells as described above are processed (e.g., isolated, purified, pre-activated, etc.) before administration. In some embodiments, the NK cell composition for administration contains certain artificial culture media or their components, such as complete RPMI-1640 medium containing L-glutamine, HEPES, NEAA, penicillin / streptomycin, and 10% human AB serum and optionally supplemented with rhIL-15 (1 ng / mL) to support survival.

[0268] Administration

[0269] Immune cells (e.g., pre-activated memory-like NK cells) can be formulated in various forms known in the art for administration to a subject. An appropriate amount of cells is administered to provide a clinical benefit, depending on the subject and / or condition, disorder, or disease to be treated. In some embodiments, the cell dose level is 0.01 - 100, 0.1 - 50, 0.1 - 20, 0.1 - 10, 0.05, 0.1, 0.2, 0.3, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90 million cells / kg. In some embodiments, the dose level is 0.5x10 6 cells / kg. In some embodiments, the dose level is 1x10 6 cells / kg. In some embodiments, the dose level does not exceed 10x106 cells / kg. As will be understood by those skilled in the art, compared with unactivated NK cells or non-memory-like pre-activated NK cells (e.g., treated only with IL-2 or IL-15 for, e.g., overnight), pre-activated memory-like NK cells can be administered at lower levels to achieve the same or more clinical benefits, or provide more clinical benefits when administered at the same level.

[0270] In many embodiments, the cells are administered via intravenous infusion. In some embodiments, a composition comprising the cells (e.g., pre-activated NK cells) is administered via infusion. In some embodiments, such a composition is administered by adoptive transfer.

[0271] In some embodiments, a subject (e.g., an AML patient) is pre-treated with a chemotherapeutic agent (e.g., on day 0) to administer the cells. For example, in some embodiments, an AML patient is pre-treated with fludarabine / cyclophosphamide on day 0.

[0272] In some embodiments, immune cells (e.g., pre-activated NK cells) are administered before an agent such as ARM. In some embodiments, they are administered concurrently with an agent such as ARM. In some embodiments, they are administered after an agent such as ARM. In some embodiments, when not administered concurrently, the immune cells (e.g., pre-activated NK cells) and an agent such as ARM are administered in a manner such that the subject is exposed to both. Certain techniques for administering NK cells are described in Miller et al., Blood 105, 3051-3057 (2005) and can be used in accordance with the present disclosure.

[0273] In some embodiments, certain cytokines are administered after or concurrently with the administration of the immune cells to support the administered immune cells. In some embodiments, a generally low dose of rhIL-2 is administered to support memory-like NK cells via the high-affinity IL-2Rαβγ it induces. See, e.g., Leong et al., Biol. Blood Marrow Transplant, 20, 463-473 (2014).

[0274] In some embodiments, for example, donor or patient - specific anti - HLA monoclonal antibodies are used to track donor memory - like NK cells in the blood of subjects with informative HLA. In some embodiments, such cells reach a peak frequency, for example, between days 7 and 14 after infusion, and may decrease in number after recipient T - cell recovery. If desired, additional doses of such NK cells can be administered (in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses can be administered). In some embodiments, at a certain time after administration (e.g., at day 7), the memory - like NK cells comprise no less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90% of the blood NK cells. In some embodiments, the level exceeds about 10%. In some embodiments, the level exceeds about 20%. In some embodiments, the level exceeds about 30%. In some embodiments, the level exceeds about 40%. In some embodiments, the level exceeds about 50%. In some embodiments, the level exceeds about 60%. In some embodiments, the level exceeds about 70%. In some embodiments, the level exceeds about 80%. In some embodiments, the level exceeds about 90%. In some embodiments, for example, compared to day 1 and later time points (e.g., day 7), the count of memory - like NK cells in the blood increases by at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 - fold. In some embodiments, the increase is at least 100 - fold. In some embodiments, the increase is at least 200 - fold. In some embodiments, the increase is at least 300 - fold. In some embodiments, the increase is at least 400 - fold. In some embodiments, the increase is at least 500 - fold. In some embodiments, the increase is at least 600 - fold. In some embodiments, the increase is at least 700 - fold. In some embodiments, the increase is at least 800 - fold. In some embodiments, the increase is at least 900 - fold. In some embodiments, the increase is at least 1000 - fold.Typically, after administration of memory-like NK cells (e.g., on days 5, 6, 7, 8, 9, 10, 11, 12, 13, and / or 14), the percentage and absolute number (count) of memory-like NK cells also increase to, for example, the percentages described above (e.g., not less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, at least 90%) and counts (e.g., 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000-fold or more; in some embodiments, 100, 200, 300, 400, 500, 600-fold or more).

[0275] In some embodiments, memory-like NK cells have enhanced function after administration, e.g., as demonstrated by increased IFN-γ production upon stimulation.

[0276] In some embodiments, memory-like NK cells have increased proliferation (Ki-67 + ) after administration (e.g., on day 3 and / or day 7).

[0277] In some embodiments, pre-activated memory-like NK cells are cytokine-induced memory-like NK cells. In some embodiments, memory-like NK cells express inhibitory KIR receptors. In some embodiments, such cells can perform one or more functions (e.g., inhibit and / or kill target cells such as cancer cells) regardless of KIR-ligand interaction.

[0278] In some embodiments, the administered immune cells (e.g., memory-like NK cells) can be detected in the blood and bone marrow of the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or longer. In some embodiments, such cells proliferate and / or expand in vivo after administration to the subject. In some embodiments, such cells differentiate in the subject and exhibit enhanced functionality against targets such as cancer cells (e.g., leukemia cells).

[0279] In some embodiments, the immune cells (e.g., pre-activated NK cells) are administered simultaneously with the ARM. In some embodiments, they are administered as a single composition. In some embodiments, they are administered as separate compositions.

[0280] In some embodiments, an appropriate amount of antibody can also be administered together with the ARM, either in the same composition or in separate compositions (and optionally can be administered before, simultaneously with, or after the ARM). In some embodiments, a composition comprising an ARM, pre-activated NK cells, and optionally an antibody or a fragment thereof is administered. In some embodiments, a composition comprising an ARM, pre-activated NK cells, and optionally IgM is administered, wherein the ARM comprises uABT. In some embodiments, the provided composition comprises a complex comprising NK cells, an antibody or a fragment thereof, and an ARM. In some embodiments, in such a complex, the CD16a receptor of the NK cell interacts with the antibody or a fragment thereof, and the antibody-binding portion of the ARM interacts with the same antibody or a fragment thereof.

[0281] 4. Exemplary ARM Agents

[0282] A variety of ARM agents can be used according to the present disclosure. In some embodiments, the ARM comprises an antibody-binding portion that interacts with the Fab region and can preferably bind and recruit antibodies (and / or fragments thereof) containing such Fab regions. In some embodiments, the ARM comprises an antibody-binding portion that interacts with the Fc region (e.g., the uABT described herein) and can bind and recruit various antibodies (and / or fragments thereof) containing such Fc regions. As will be understood by those skilled in the art, the antibodies (and / or fragments thereof) recruited by such ARMs can contain different Fab regions and can have different specificities. In some embodiments, no single recruited antibody (or fragment thereof) has more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90% of the total recruited antibodies and their fragments.

[0283] In certain embodiments, a useful ARM is a compound of Formula I:

[0285] or a pharmaceutically acceptable salt thereof, wherein:

[0286] ABT is an antibody-binding portion;

[0287] L is a bivalent linker portion that connects ABT to TBT; and

[0288] TBT is a target-binding portion.

[0289] In some embodiments, a useful ARM is a compound of Formula I-a or a salt thereof. In some embodiments, a useful ARM is a compound of Formula I-b or a salt thereof.

[0290] In certain embodiments, useful ARMs are compounds of Formula II or pharmaceutically acceptable salts thereof, wherein:

[0291] R 1 、R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8-10 membered bicyclic aromatic carbocyclic, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0292] R 1 and R 1' optionally together with the intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocarbocyclic ring or a 4-8 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0293] R 3 and R 3’ optionally together with the intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocarbocyclic ring or a 4-8 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0294] R 5 group and the R 5’ group attached to the same carbon atom optionally together with the intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocarbocyclic ring or a 4-8 membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0295] two R 5 groups optionally together with the intervening atoms form a C 1-10 divalent straight or branched chain saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -, or -Cy 1 -, wherein each -Cy 1 - is independently a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0296] R 1’ 、R3’ and R 5’ each independently is hydrogen or C 1-3 aliphatic;

[0297] R 2 、R 4 and R 6 each independently is hydrogen or C 1-4 aliphatic, or:

[0298] R 2 and R 1 optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0299] R 4 and R 3 optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

[0300] R 6 group and its adjacent R 5 group optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0301] L 1 is a linking

[0302] trivalent linker moiety;

[0303] L 2 is a covalent bond or C 1-10 divalent straight-chain or branched-chain saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -,

[0304] TBT is a target-binding moiety; and

[0305] m and n each independently is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0306] In certain embodiments, a useful ARM is a compound of formula III:

[0308] or a pharmaceutically acceptable salt thereof, wherein:

[0309] each R 7is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0310] R 7 groups and the R 7’ groups optionally together with the intervening carbon atom form a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0311] Each R 7' is independently hydrogen or C 1-3 aliphatic;

[0312] Each R 8 is independently hydrogen or C 1-4 aliphatic, or:

[0313] R 8 groups and its adjacent R 7 groups optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0314] R 9 is hydrogen, C 1-3 aliphatic or -C(O)C 1-3 aliphatic;

[0315] L 3 is a linker

[0316] TBT is a target binding moiety; and

[0317] o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0318] antibody binding moiety

[0319] Various antibody binding moieties are known in the art and can be used in accordance with the present disclosure.

[0320] In some embodiments, the antibody binding moiety interacts primarily with the Fab region. In some embodiments, the antibody binding moiety interacts primarily with an antibody and / or a fragment thereof that comprises certain Fab structures and / or is directed against certain antigens.

[0321] In some embodiments, the antibody binding portion interacts with the Fc region. In some embodiments, the antibody binding portions described herein (e.g., uABT) interact with the Fc region and can recruit Fc regions that are linked to Fab regions having different structures and / or antigen specificities. In some embodiments, useful agents comprise a universal antibody binding portion that can bind antibodies having different Fab regions and different specificities. In some embodiments, the antibody binding portion is a universal antibody binding portion that binds to the Fc region. In some embodiments, the binding of the antibody binding portion to an antibody (or a fragment thereof) (e.g., the binding of uABT to the Fc region) can occur simultaneously with the binding of an Fc receptor (e.g., CD16a) to the same antibody (or a fragment thereof) (e.g., in the case of binding of uABT to Fc, it can occur at different positions / amino acid residues of the same Fc region). In some embodiments, after binding of the universal antibody binding portion, the Fc region can still interact with the Fc receptor and perform one or more or all of its immunological activities, including recruitment of immune cells (e.g., effector cells such as NK cells), and / or triggering, generating, encouraging, and / or enhancing immune system activities against target cells, tissues, objects, and / or entities, e.g., antibody-dependent cell-mediated cytotoxicity (ADCC) and / or ADCP.

[0322] A variety of universal antibody binding portions can be used according to the present disclosure, and many techniques (e.g., those described in the Examples) can be used to identify and / or evaluate universal antibody binding portions. In some embodiments, the universal antibody binding portion comprises one or more amino acid residues, each of which is independently natural or non-natural. In some embodiments, the universal antibody binding portion has a structure

[0323] In some embodiments, -(Xaa)z- is or comprises [X 1 p1 [X 2 p2 -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -[X 13 p13 -[X 14 p14 [X 15 p15 [X 16 p16 , where X 1 、X​​​​​​2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 are each independently an amino acid residue, for example, an amino acid residue of formula A-I, and p1, p2, p13, p14, p15 and p16 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 are each independently an amino acid residue of an amino acid of formula A-I. In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 are each independently a natural amino acid residue. In some embodiments, one or more of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 are independently one or more non-natural amino acid residues as described in the present disclosure.

[0324] In some embodiments, the peptide unit comprises a functional group in an amino acid residue that can react with a functional group of another amino acid residue. In some embodiments, the peptide unit comprises an amino acid residue having a side chain that comprises a functional group that can react with another functional group of the side chain of another amino acid residue to form a linkage (e.g., see the compounds in Table 1). In some embodiments, one functional group of one amino acid residue is linked to a functional group of another amino acid residue to form a linkage (or bridge). The linkage is bonded to the backbone atoms of the peptide unit and does not comprise backbone atoms. In some embodiments, the peptide unit comprises a linkage formed by two side chains of non-adjacent amino acid residues. In some embodiments, the linkage is bonded to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, both of the backbone atoms bonded to the linkage are carbon atoms. In some embodiments, the linkage has an L b structure, where L b is as described in the present disclosure as L a , where L a is not a covalent bond. In some embodiments, L a comprises -Cy-. In some embodiments, L a comprises -Cy-, where -Cy- is an optionally substituted heteroaryl. In some embodiments, -Cy- is

[0325] In some embodiments, the two amino acid residues bonded to the linkage are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more than 15 amino acid residues (excluding the two amino acid residues bonded to the linkage) therebetween. In some embodiments, the number is 1. In some embodiments, the number is 2. In some embodiments, the number is 3. In some embodiments, the number is 4. In some embodiments, the number is 5. In some embodiments, the number is 6. In some embodiments, the number is 7. In some embodiments, the number is 8. In some embodiments, the number is 9. In some embodiments, the number is 10. In some embodiments, the number is 11. In some embodiments, the number is 12. In some embodiments, the number is 13. In some embodiments, the number is 14. In some embodiments, the number is 15.

[0326] In some embodiments, p1, p2, p13, p14, p15, and p16 are each 0. In some embodiments, -(Xaa)z- is or comprises -X 3 X 4 X 5 X 6 X 7 X 8 X9 X 10 X 11 X 12 -, wherein:

[0327] X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 are each independently an amino acid residue;

[0328] X 6 is Xaa A or Xaa P ;

[0329] X 9 is Xaa N ; and

[0330] X 12 is Xaa A or Xaa P .

[0331] In some embodiments, X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 are each independently an amino acid residue of an amino acid of formula A-I as described in the present disclosure. In some embodiments, X 5 is Xaa A or Xaa P . In some embodiments, X 5 is Xaa A . In some embodiments, X 5 is Xaa P . In some embodiments, X 5 is an amino acid residue whose side chain contains an optionally substituted saturated ring, partially saturated ring or aromatic ring. In some embodiments, X 5 is

[0332] In some embodiments, -(Xaa)z- is or contains -X 3 X 4 X 5 X 6 X7 X 8 X 9 X 10 X 11 X 12 -, wherein:

[0333] X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently an amino acid residue;

[0334] At least two amino acid residues are linked by one or more linkers L b connected;

[0335] L b is selected from C 1 -C 20 an aliphatic or C with 1-5 heteroatoms 1 -C 20 an optionally substituted divalent group of heteroaliphatic, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, or -C(O)O-, wherein L b is bonded to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms;

[0336] X 6 is Xaa A or Xaa P ;

[0337] X 9 is Xaa N ; and

[0338] X 12 is Xaa A or Xaa P .

[0339] In some embodiments, X 3 , X 4, X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently amino acid residues of the amino acids of formula A-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, X 5 and X 10 are linked by L b . In some embodiments, there is a linking L b . In some embodiments, X 6 is Xaa A . In some embodiments, X 6 is XaaP. In some embodiments, X 6 is His. In some embodiments, X 9 is Asp. In some embodiments, X 9 is Glu. In some embodiments, X 12 is Xaa A . In some embodiments, X 12 is

[0340] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -, wherein:

[0341] X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently amino acid residues;

[0342] at least two amino acid residues are linked by one or more linkings L b ;

[0343] Lb is selected from C 1 -C 20 -aliphatic or C with 1-5 heteroatoms 1 -C 20 -heteroaliphatic optionally substituted divalent group, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -、-Cy-、-O-、-S-、-S-S-、-N(R’)-、-C(O)-、-C(S)-、-C(NR’)-、-C(O)N(R’)-、-N(R’)C(O)N(R’)-、-N(R’)C(O)O-、-S(O)-、-S(O) 2 -、-S(O) 2 -N(R’)-、-C(O)S-、or -C(O)O-, where L b is bonded to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms;

[0344] X 4 is Xaa A ;

[0345] X 5 is Xaa A or Xaa P ;

[0346] X 8 is Xaa N ; and

[0347] X 11 is Xaa A .

[0348] In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently amino acid residues of an amino acid of formula A-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, there is one linking L b . In some embodiments, X 2 and X 12 are linked by L b . In some embodiments, L b is -CH2 -S-S-CH 2 -. In some embodiments, L b is -CH 2 -CH 2 -S-CH 2 -. In some embodiments, L b is

[0349] In some embodiments, L b connects the two α-carbon atoms of two different amino acid residues. In some embodiments, X 4 is Xaa A . In some embodiments, X 4 is Tyr. In some embodiments, X 5 is Xaa A . In some embodiments, X 5 is XaaP. In some embodiments, X 5 is His. In some embodiments, X 8 is Asp. In some embodiments, X 8 is Glu. X 11 is Tyr. In some embodiments, X 2 and X 12 are both Cys, and the two -SH groups of their side chains form -S-S- (L b is -CH 2 -S-S-CH 2 -). In some embodiments, X 3 , X 6 , X 9 and X 10 are each independently Xaa H . In some embodiments, X 3 is Xaa H . In some embodiments, X 3 is Ala. In some embodiments, X 6 is Xaa H . In some embodiments, X 6 is Leu. In some embodiments, X 9 is Xaa H . In some embodiments, X 9 is Leu. In some embodiments, X 9 is

[0350] In some embodiments, -(Xaa)z- is or contains -X 2 X 3 X 4 X 5 X6 X 7 X 8 X 9 X 10 X 11 X 12 -, wherein:

[0351] X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 are each independently an amino acid residue;

[0352] At least two amino acid residues are linked by one or more linkers L b connected;

[0353] L b is selected from C 1 -C 20 aliphatic or C with 1-5 heteroatoms 1 -C 20 optionally substituted divalent group of heteroaliphatic, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, or -C(O)O-, where L b is bonded to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms;

[0354] X 5 is Xaa A or Xaa P ;

[0355] X 8 is Xaa N ; and

[0356] X 11 is Xaa A .

[0357] In some embodiments, X 2 、X3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently an amino acid residue of an amino acid of formula A-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, there is one linkage L b . In some embodiments, there are two or more linkages L b . In some embodiments, there are two linkages L b . In some embodiments, X 2 and X 12 are linked by L b . In some embodiments, X 4 and X 9 are linked by L b . In some embodiments, X 4 and X 10 are linked by L b . In some embodiments, L b is -CH 2 -S-S-CH 2 -. In some embodiments, L b is

[0358] In some embodiments, X 5 is Xaa A . In some embodiments, X 5 is XaaP. In some embodiments, X 5 is His. In some embodiments, X 8 is Asp. In some embodiments, X 8 is Glu. In some embodiments, X 11 is Tyr. In some embodiments, X 11 is

[0359] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12X 13 X 14 X 15 X 16 -, wherein:

[0360] X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 、X 14 、X 15 and X 16 are each independently an amino acid residue;

[0361] At least two amino acid residues are linked by a bond L b connected;

[0362] L b is selected from C 1 -C 20 aliphatic or C with 1 - 5 heteroatoms 1 -C 20 optionally substituted divalent heteroaliphatic group, wherein one or more methylene units of said group are optionally and independently replaced by -C(R') 2 -,-Cy-,-O-,-S-,-S-S-,-N(R')-,-C(O)-,-C(S)-,-C(NR')-,-C(O)N(R')-,-N(R')C(O)N(R')-,-N(R')C(O)O-,-S(O)-,-S(O) 2 -,-S(O) 2 N(R')-,-C(O)S- or -C(O)O-, where L b is bonded to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms;

[0363] X 3 is Xaa N ;

[0364] X 6 is Xaa A ;

[0365] X 7 is Xaa A or Xaa P ;

[0366] X9 is Xaa N ; and

[0367] X 13 is Xaa A .

[0368] In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently an amino acid residue of an amino acid of formula A-I as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, there is one linkage L b . In some embodiments, there are two or more linkages L b . In some embodiments, there are two linkages L b . In some embodiments, X 2 is linked to X b via L 16 . In some embodiments, X 4 is linked to X b via L 14 . In some embodiments, X 2 and X 16 are both Cys, and the two -SH groups of their side chains form -S-S- (L b is -CH 2 -S-S-CH 2 -). In some embodiments, X 4 and X 14 are both Cys, and the two -SH groups of their side chains form -S-S- (L b is -CH 2 -S-S-CH 2 -). In some embodiments, L b connects the two α-carbon atoms of two different amino acid residues. In some embodiments, X 3 is Asp. In some embodiments, X 3 is Glu. In some embodiments, X 5 is Xaa H . In some embodiments, X 5 is Ala. In some embodiments, X 6 is XaaA . In some embodiments, X 6 is Tyr. In some embodiments, X 7 is Xaa A . In some embodiments, X 7 is Xaa P . In some embodiments, X 7 is His. In some embodiments, X 8 is Xaa H . In some embodiments, X 8 is Ala. In some embodiments, X 9 is Gly. In some embodiments, X 10 is Asp. In some embodiments, X 10 is Glu. In some embodiments, X 11 is Xaa H . In some embodiments, X 11 is Leu. In some embodiments, X 12 is Xaa H . In some embodiments, X 12 is Val. In some embodiments, X 13 is Xaa A . In some embodiments, X 13 is Tyr. In some embodiments, X 15 is an amino acid residue containing a polar uncharged side chain (e.g., at physiological pH, a "polar uncharged amino acid residue", Xaa L ). In some embodiments, X 15 is Val. In some embodiments, p1 is 1. In some embodiments, in some embodiments, X 1 is Xaa N . In some embodiments, X 1 is Asp. In some embodiments, X 1 is Glu.

[0369] As will be appreciated by those skilled in the art, one amino acid residue can be replaced by another amino acid residue having similar properties. For example, one Xaa H (e.g., Val, Leu, etc.) can be replaced by another Xaa H (e.g., Leu, Ile, Ala, etc.), one Xaa A can be replaced by another Xaa A , one Xaa P can be replaced by another Xaa P , one Xaa N can be replaced by another XaaN Alternatively, one Xaa L can be replaced by another Xaa L and so on.

[0370] In some embodiments, the antibody binding portion (e.g., the common antibody binding portion) is the common antibody binding portion of the compounds in Table 1. In some embodiments, the antibody binding portion (e.g., the common antibody binding portion) is or comprises optionally substituted.

[0380] In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-1. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-2. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-3. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-4. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-5. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-6. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-7. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-8. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-9. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-10. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-11. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-12. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-13. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-14. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-15. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-16. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-17. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-18. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-19. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-20. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-21. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-22. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-23. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-24. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-25. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-26. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-27. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-28. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-29. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-30. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-31. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-32.In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-33. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-34. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-35. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-36. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-37. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-38. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-39. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-40. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-41. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-42. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-43. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-44. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-45. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-46. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-47. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-48. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-49. In some embodiments, it is unsubstituted. In some embodiments, it is substituted.

[0381] In some embodiments, the universal antibody binding portion comprises a peptide unit and is linked to the linker portion through the C-terminus of the peptide unit. In some embodiments, it is linked to the linker portion through the N-terminus of the peptide unit. In some embodiments, it is linked through a side chain group of the peptide unit.

[0382] In some embodiments, the antibody binding portion (e.g., the universal antibody binding portion) is or comprises a small molecule entity having a molecular weight of, for example, less than 10,000, 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1,500, 1,000, etc. Suitable such antibody binding portions include small molecule Fc binding portions, e.g., those described in US 9,745,339, US 20130131321, etc.

[0383] As will be understood by those skilled in the art, antibodies having various properties and activities (e.g., antibodies that recognize different antigens, have optional modifications, etc.) can be recruited by the antibody-binding moieties described in the present disclosure. In some embodiments, such antibodies include administering antibodies to a subject, e.g., for therapeutic purposes. In some embodiments, the antibodies recruited by the antibody-binding moiety include antibodies against different antigens. In some embodiments, the antibodies recruited by the antibody-binding moiety include antibodies whose antigens are not present on the surface or cell membrane of a target cell (e.g., a target cell such as a cancer cell). In some embodiments, the antibodies recruited by the antibody-binding moiety include antibodies that do not target antigens present on the surface or cell membrane of a target (e.g., a target cell such as a cancer cell). In some embodiments, antigens on the surface of a target cell may interfere with the structure, conformation, and / or one or more properties and / or activities of an antibody recruited to bind such antigens. In some embodiments, as will be understood by those skilled in the art, the provided techniques include a universal antibody-binding moiety that recruits antibodies with different specificities, and no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the recruited antibodies target the same antigen, protein, lipid, carbohydrate, etc. Among other things, one advantage of the present disclosure is that the provided techniques that include a universal antibody-binding moiety can utilize different antibody repertoires, such as the antibody repertoire present in serum. In some embodiments, the universal antibody-binding moieties of the present disclosure (e.g., those in an ARM) are contacted with a plurality of antibodies, and no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the plurality of antibodies target the same antigen, protein, lipid, carbohydrate, etc.

[0384] Amino acid

[0385] In some embodiments, useful compounds and agents (e.g., an ARM) can include one or more amino acid moieties, e.g., amino acid moieties in a universal antibody-binding moiety, a linker moiety, etc. The amino acid moiety can be a natural amino acid or a non-natural amino acid. In some embodiments, the amino acid has the structure of Formula A-I:

[0386] NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH,

[0387] A-I

[0388] or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, the amino acid residue has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -CO- structure.

[0389] In some embodiments, L a1 is a covalent bond. In some embodiments, the compound of formula A-I has NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH structure.

[0390] In some embodiments, L a2 is a covalent bond. In some embodiments, the compound of formula A-I has NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH structure.

[0391] In some embodiments, L a1 is a covalent bond and L a2 is a covalent bond. In some embodiments, the compound of formula A-I has NH(R a1 )-C(R a2 )(R a3 )-COOH structure.

[0392] In some embodiments, L a is a covalent bond. In some embodiments, L a is an optionally substituted C 1-6 divalent aliphatic. In some embodiments, L a is an optionally substituted C 1-6 alkylene. In some embodiments, L a is -CH 2 -. In some embodiments, L a is -CH 2 CH 2 -. In some embodiments, L a is -CH 2 CH 2 CH 2 -.

[0393] In some embodiments, R' is R. In some embodiments, R a1is R, where R is as described in the present disclosure. In some embodiments, R a2 is R, where R is as described in the present disclosure. In some embodiments, R a3 is R, where R is as described in the present disclosure. In some embodiments, R a1 、R a2 and R a3 are each independently R, where R is as described in the present disclosure.

[0394] In some embodiments, R a1 is hydrogen. In some embodiments, R a2 is hydrogen. In some embodiments, R a3 is hydrogen. In some embodiments, R a1 is hydrogen, and at least one of R a2 and R a3 is hydrogen. In some embodiments, R a1 is hydrogen, one of R a2 and R a3 is hydrogen, and the other is not hydrogen.

[0395] In some embodiments, R a2 is -L a -R, where R is as described in the present disclosure. In some embodiments, R a2 is -L a -R, where R is an optionally substituted group selected from C 3-30 alicyclic, C 5-30 aryl, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R a2 is -L a -R, where R is an optionally substituted group selected from C 6-30 aryl and 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R a2 is the side chain of an amino acid. In some embodiments, R a2 is the side chain of a standard amino acid.

[0396] In some embodiments, R a3 is -L a -R, where R is as described in the present disclosure. In some embodiments, R a3 is -L a -R, where R is an optionally substituted group selected from C 3-30 alicyclic, C 5-30An aryl group, a 5- to 30-membered heteroaryl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R a3 is -L a -R, where R is an optionally substituted group selected from C 6-30 an aryl group and a 5- to 30-membered heteroaryl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R a3 is the side chain of an amino acid. In some embodiments, R a3 is the side chain of a standard amino acid.

[0397] In some embodiments, R is a cyclic group. In some embodiments, R is an optionally substituted C 3-30 alicyclic group. In some embodiments, R is cyclopropyl.

[0398] In some embodiments, R is an aromatic group, and the amino acid residue of the amino acid of formula A-I is Xaa A . In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is a phenyl group. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is 4-trifluoromethylphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 14-membered heteroaryl group having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is

[0399] In some embodiments, R' is -COOH. In some embodiments, the compound and the amino acid residue of the amino acid of formula A-I are Xaa N .

[0400] In some embodiments, R' is -NH 2 . In some embodiments, the compound of the amino acid residue of the amino acid of formula A-I is Xaa P .

[0401] In some embodiments, R a2 or R a3 is R, where R is C 1-20 aliphatic as described in the present disclosure. In some embodiments, the compound of the amino acid residue of the amino acid of formula A-I is Xaa H . In some embodiments, R is -CH 3. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is cyclopropyl.

[0402] In some embodiments, R a1 , R a2 and R a3 two or more of are R and together form an optionally substituted ring as described in the present disclosure.

[0403] In some embodiments, R a1 as well as R a2 and R a3 one of is R and together form an optionally substituted 3- to 6-membered ring that has no additional ring heteroatoms other than the nitrogen atom bonded to R a1 . In some embodiments, the ring formed is a 5-membered ring as in proline.

[0404] In some embodiments, R a2 and R a3 are R and together form an optionally substituted 3- to 6-membered ring as described in the present disclosure. In some embodiments, R a2 and R a3 are R and together form an optionally substituted 3- to 6-membered ring having one or more nitrogen ring atoms. In some embodiments, R a2 and R a3 are R and together form an optionally substituted 3- to 6-membered ring having one and no more than one ring heteroatom that is a nitrogen atom. In some embodiments, the ring is a saturated ring.

[0405] In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is a non-natural amino acid. In some embodiments, the amino acid is an α-amino acid. In some embodiments, the amino acid is a β-amino acid.

[0406] Target

[0407] In some embodiments, the present disclosure provides techniques for selectively directing an agent (e.g., an ARM compound), an antibody, and an immune cell (e.g., an NK cell) comprising a target-binding moiety to a desired target site comprising one or more targets. As will be understood by those skilled in the art, the techniques provided can be used for various types of targets.

[0408] In some embodiments, the target is damaged or defective tissue. In some embodiments, the target is damaged tissue. In some embodiments, the target is defective tissue. In some embodiments, the target is associated with a disease, disorder, or condition (e.g., cancer, wound, etc.). In some embodiments, the target is a tumor. In some embodiments, the target is or comprises diseased cells. In some embodiments, the target is or comprises cancer cells. In some embodiments, the target is a foreign object. In some embodiments, the target is or comprises an infectious pathogen. In some embodiments, the target is a microorganism. In some embodiments, the target is or comprises bacteria. In some embodiments, the target is or comprises a virus.

[0409] In many embodiments, the target is tissue and / or cells associated with a disease, disorder, or condition, particularly various types of cancer. In some embodiments, the target is or comprises cancer cells. Among other things, the present disclosure provides techniques that are particularly suitable for selectively targeting cancer cells via the immune system, e.g., by recruiting antibodies (e.g., endogenous antibodies) and immune cells (e.g., NK cells), by using an ARM.

[0410] In many embodiments, the target is a cell of a cancer or a proliferative disorder, condition, or disease. In some embodiments, the cancer or proliferative disorder, condition, or disease is selected from a benign tumor, a malignant tumor, a solid tumor, a brain cancer, a kidney cancer, a liver cancer, an adrenal cancer, a bladder cancer, a breast cancer (breast), a gastric cancer, a stomach tumor, an ovarian cancer, a colon cancer, a rectal cancer, a prostate cancer, a pancreatic cancer, a lung cancer, a vaginal cancer, a cervical cancer, a testicular cancer, a genitourinary cancer, an esophageal cancer, a laryngeal cancer, a skin cancer, a bone or thyroid cancer, a sarcoma, a glioblastoma, a neuroblastoma, multiple myeloma, a gastrointestinal cancer (especially a colon cancer or a colorectal adenoma), a head and neck tumor, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, neoplasia with epithelial characteristics, an adenoma, an adenocarcinoma, a keratoacanthoma, an epidermoid carcinoma, a large cell carcinoma, a non-small cell lung cancer, a lymphoma, Hodgkin's disease and non-Hodgkin's disease, a breast cancer (mammary carcinoma), a follicular carcinoma, an undifferentiated carcinoma, a papillary carcinoma, a seminoma, a melanoma, a hematological malignancy (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma).

[0411] Target sites typically contain one or more physical, chemical, and / or biological markers, which can be used, for example, by the target-binding portion of a compound (e.g., an ARM) to selectively recruit an antibody and / or its fragment, and / or to recruit immune cells to the target.

[0412] In some embodiments, the cells of the target site contain one or more characterizing agents that can be used for targeting. In some embodiments, such agents are proteins and / or their fragments. In some embodiments, such agents are antigens specifically associated with a disease, disorder, or condition.

[0413] For example, in some embodiments, cancer cells can contain one or more tumor-specific antigens or tumor-associated antigens. The target-binding portion as described in the present disclosure can selectively bind to such markers. In some embodiments, the target-binding portion of the present disclosure is a small molecule for binding to cell surface proteins and / or intracellular proteins.

[0414] In some embodiments, the characterizing agent (e.g., the characterizing agent of a cell having a target site, etc.) is or contains saccharides, such as those on the cell surface, in glycosylated proteins, etc. In some embodiments, the characterizing agent is or contains lipids.

[0415] In some embodiments, the characterizing agent (e.g., the characterizing agent of a cell having a target site, etc.) is extracellular. In some embodiments, the characterizing agent is an extracellular protein. In some embodiments, the characterizing agent is on the cell surface. In some embodiments, the characterizing agent is a protein present on the cell surface. For example, in many tumor tissues, cell surface and / or extracellular mucins exhibit different glycosylation levels and / or patterns and can be used for targeting.

[0416] In some embodiments, the target site (e.g., diseased tissue, etc.) has one or more physical, biological, and / or chemical properties that can be utilized by the target-binding portion. In some embodiments, such a property is pH. In some embodiments, such a property is the concentration of one or more chemical substances. For example, the tumor microenvironment is typically hypoxic and / or acidic (e.g., pH 6.5 - 6.9 versus 7.2 - 7.4).

[0417] In some embodiments, the target is or contains a peptide or its fragment. In some embodiments, the target is or contains a protein or its fragment. In some embodiments, the target is avidin. In some embodiments, the target is streptavidin. In some embodiments, the target is or contains an antigen. In some embodiments, the target is or contains a tumor-specific antigen. In some embodiments, the target is or contains a tumor-associated antigen (TAA).

[0418] In some embodiments, the tumour-associated antigen is or comprises a carbohydrate. In some embodiments, the provided target-binding moiety targets such TAAs. In some embodiments, the carbohydrate is part of a glycoprotein. In some embodiments, the carbohydrate is part of a glycolipid. Many disorders, afflictions, and diseases (e.g., various types of cancer) are associated with abnormal glycosylation. In some embodiments, tumour-associated carbohydrate antigens (TACAs) include, and / or are associated with, altered sialic acid expression, altered Lewis antigen expression, altered ganglioside expression, etc. In some embodiments, the target-binding moieties of the present disclosure can target various types of TACAs, including those described in the art, e.g., in Chua and Durrant, Monoclonal Antibodies Against Tumour-Associated Carbohydrate Antigens, Carbohydrate Mahmut Caliskan, IntechOpen, DOI:10.5772 / 66996.

[0419] In some embodiments, the tumor-associated antigen is a cell surface receptor. In some embodiments, the TAA is selected from BMPR1B (bone morphogenetic protein receptor, type IB, Genbank accession number NM_001203); E16 (LAT1, SLC7A5, Genbank accession number NM_003486); STEAP1 (six-transmembrane prostate epithelial antigen, Genbank accession number NM_012449); 0772P (CA125, MUC16, Genbank accession number AF361486); MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession number NM_005823); Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate) member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession number NM_006424); Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, semaphorin 5B homolog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession number AB040878); PSCA hlg (2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628); ETBR (endothelin B receptor, Genbank accession number AY275463); MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number NM_017763); STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMPI, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, six-transmembrane prostate epithelial antigen 2, six-transmembrane prostate protein, Genbank accession number AF455138); TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M member 4, Genbank accession number NM_017636); CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession number NP_003203 or NM_003212); CD21 (CR2 (complement receptor 2) or C3DR (C3d / Epstein-Barr virus receptor) or Hs.73792, Genbank accession number M26004); CD79b (CD79B, CD79.β., IGb (immunoglobulin-associated protein β), B29, Genbank accession number NM.sub.-000626); FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain-containing phosphatase-anchoring protein 1a), SPAP1B, SPAP1C, Genbank accession number NM.sub.-030764); HER2 (Genbank accession number M1730); NCA (Genbank accession number M18728); MDP (Genbank accession number BC017023); IL20Rα (Genbank accession number AF184971); Brevican (Genbank accession number AF229053); EphB2R (Genbank accession number NM.sub.-004442); ASLG659 (Genbank accession number AX092328); PSCA (Genbank accession number AJ297436); GEDA (Genbank accession number AY260763); BAFF--R (B cell activation factor receptor, BLyS receptor 3, BR3, NP.sub.-443177.1); CD22 (B cell receptor CD22-B isotype, NP.sub.-001762.1); CD79a (CD79A, CD79.α., immunoglobulin-associated protein α, B cell-specific protein that covalently interacts with Igβ (CD79B) and forms a complex with Ig M molecules on the surface, transducing signals involved in B cell differentiation, Genbank accession number NP.sub.--001774.1); CXCR5 (Burkitt lymphoma receptor 1, G protein-coupled receptor that is activated by the CXCL13 chemokine, plays a role in lymphocyte migration and humoral defense, and plays a role in the development of HIV-2 infection and possibly AIDS, lymphoma, myeloma, and leukemia, Genbank accession number NP.sub.-001707.1); HLA-DOB (β subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes, Genbank accession number NP.sub.-002111.1); P2X5 (purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP that may be involved in synaptic transmission and neurogenesis, and whose deficiency may contribute to the pathophysiology of idiopathic detrusor instability, Genbank accession number NP.sub.-002552.2); CD72 (B cell differentiation antigen CD72, Lyb-2, Genbank accession number NP.sub.-001773.1); LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein of the leucine-rich repeat (LRR) family that regulates B cell activation and apoptosis, loss of function of which is associated with increased disease activity in patients with systemic lupus erythematosus, Genbank accession number NP_sub.--005573.1); FcRH1 (Fc receptor-like protein 1, a putative receptor for the immunoglobulin Fc domain, containing a C2-type Ig-like domain and an ITAM domain, which may play a role in B lymphocyte differentiation, Genbank accession number NP-443170.1); IRTA2 (immunoglobulin superfamily receptor translocation-associated 2, a putative immunoreceptor that may play a role in B cell development and lymphoma genesis, dysregulation of this gene caused by translocation occurs in some B cell malignancies, Genbank accession number NP_sub.-112571.1); and TENB2 (putative transmembrane proteoglycan, related to the EGF / heregulin family of growth factors and follistatin, Genbank accession number AF 179274).

[0420] In some embodiments, the target is or comprises a nucleic acid.

[0421] In some embodiments, the target is or comprises a lipid.

[0422] In some embodiments, the target is or comprises a carbohydrate. In some embodiments, the target is or comprises a carbohydrate associated with a disease, disorder, or condition. In some embodiments, the target is or comprises a carbohydrate associated with cancer, e.g., a carbohydrate that is a glycan modification of a protein, e.g., on the surface of or extracellular to a cancer cell.

[0423] Target binding moiety

[0424] A variety of types and chemical classes of target-binding moieties can be used in accordance with the present disclosure, and a variety of techniques (e.g., assays, reagents, kits, etc.) for identifying and / or evaluating the properties of the target-binding moieties can be used in accordance with the present disclosure. Generally, the target-binding moiety interacts with the target site through one or more physical, biological, and / or chemical properties. In some embodiments, the target-binding moiety binds to a characterizing agent as described in the present disclosure. In some embodiments, the target-binding moiety binds to a surface, extracellular, and / or intracellular protein, carbohydrate, and / or nucleic acid. In some embodiments, the target-binding moiety binds to a surface protein of a target cell. In some embodiments, the target-binding moiety is a small molecule moiety. In some embodiments, the target-binding moiety is an antibody agent. In some embodiments, the target-binding moiety is a nucleic acid agent, such as an aptamer. In some embodiments, the target-binding moiety is a lipid moiety. Certain types of target-binding moieties are described below; those skilled in the art will understand that other types of target-binding moieties (including many target-binding moieties known in the art) can be used in accordance with the present disclosure.

[0425] In some embodiments, the targeting-binding moiety binds to the target through one or more proteins, lipids, nucleic acids, carbohydrates, small molecules, etc. in the target. For example, in some embodiments, the target-binding moiety binds to a tumor-specific antigen of a target cancer cell. In some embodiments, the tumor-specific antigen is or comprises a carbohydrate or a fragment thereof. In some embodiments, the tumor-specific antigen is or comprises a protein or a fragment thereof.

[0426] In some embodiments, the target-binding moiety binds to a cell surface protein, carbohydrate, or lipid. In some embodiments, the target-binding moiety binds to CD19. In some embodiments, the target-binding moiety binds to CD20. In some embodiments, the target-binding moiety binds to CD22. In some embodiments, the target-binding moiety binds to CD30. In some embodiments, the target-binding moiety binds to CD33. In some embodiments, the target-binding moiety binds to CD123.

[0427] a. Small molecules

[0428] In some embodiments, the target binding moiety is a small molecule moiety. In some embodiments, the molecular weight of the small molecule moiety does not exceed 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, 900, 800, 700, or 600. In some embodiments, the molecular weight of the small molecule moiety does not exceed 8000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 7000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 6000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 5000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 4000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 3000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 2000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 1500. In some embodiments, the molecular weight of the small molecule moiety does not exceed 1000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 900. Among other things, the present disclosure encompasses the recognition that a small molecule target binding moiety may be capable of binding to markers outside, on the surface, and / or inside a target (e.g., a cancer cell).

[0429] In some embodiments, the small molecule target binding moiety is or comprises a moiety that selectively binds to a protein or a fragment thereof (e.g., a cancer antigen). For example, in some embodiments, the target binding moiety is or comprises a moiety that selectively binds to prostate specific membrane antigen (PSMA). In some embodiments, the target binding moiety is or comprises

[0430] In some embodiments, the small molecule target binding moiety is or comprises a biotin moiety. In some embodiments, the small molecule target binding moiety is or comprises

[0431] b. Peptide agent

[0432] In some embodiments, the target binding moiety is or comprises a peptide agent. In some embodiments, the target binding moiety is a peptide moiety. In some embodiments, the peptide moiety can be linear or cyclic. In some embodiments, the target binding moiety is or comprises a cyclic peptide moiety. Various peptide target binding moieties are known in the art and can be used in accordance with the present disclosure.

[0433] In some embodiments, the target binding moiety is or comprises a peptide aptamer agent.

[0434] c. Aptamer agent

[0435] In some embodiments, the target binding moiety is or comprises a nucleic acid agent. In some embodiments, the target binding moiety is or comprises an oligonucleotide moiety. In some embodiments, the target binding moiety is or comprises an aptamer agent. Various aptamer agents are known in the art or can be readily developed using conventional techniques and can be used in the provided technologies in accordance with the present disclosure.

[0436] Linker moiety

[0437] In some embodiments, the antibody binding moiety is optionally linked to the target binding moiety via a linker moiety. Various types and / or linker moieties for various purposes can be used in accordance with the present disclosure, e.g., linker moieties in antibody-drug conjugates and the like.

[0438] The linker moiety can be bivalent or multivalent. In some embodiments, the linker moiety is bivalent. In some embodiments, the linker is multivalent and links more than two moieties.

[0439] In some embodiments, the linker moiety is L. In some embodiments, L is a covalent bond or an optionally substituted bivalent or multivalent linear or branched C comprising one or more aliphatic, aryl, heteroaliphatic having 1 - 20 heteroatoms, heteroaromatic having 1 - 20 heteroatoms, or any combination thereof 1-100 group, wherein one or more methylene units of the group are optionally and independently replaced by C 1-6 alkylene, C 1-6 alkenylene, divalent C having 1 - 5 heteroatoms 1-6 heteroaliphatic group, -C≡C-, -Cy-, -C(R’) 2 -, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -C(O)C(R’) 2 N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, -C(O)O-, -P(O)(OR’)-, -P(O)(SR’)-, -P(O)(R’)-, -P(O)(NR’)-, -P(S)(OR’)-, -P(S)(SR’)-, -P(S)(R’)-, -P(S)(NR’)-, -P(R’)-, -P(OR’)-, -P(SR’)-, -P(NR’)-, or -[(-O-C(R’) 2 -C(R’) 2 -) n-substitution, where n is from 1 to 20.

[0440] In some embodiments, L is divalent. In some embodiments, L is a divalent or optionally substituted linear or branched group selected from C 1-00 aliphatic and C with 1 - 50 heteroatoms 1-100 heteroaliphatic, wherein one or more methylene units of said group are optionally and independently replaced by C 1-6 alkylene, C 1-6 alkenylene, divalent C with 1 - 5 heteroatoms 1-6 heteroaliphatic group, -C≡C-, -Cy-, -C(R’) 2 -, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -C(O)C(R’) 2 N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, -C(O)O-, -P(O)(OR’)-, -P(O)(SR’)-, -P(O)(R’)-, -P(O)(NR’)-, -P(S)(OR’)-, -P(S)(SR’)-, -P(S)(R’)-, -P(S)(NR’)-, -P(R’)-, -P(OR’)-, -P(SR’)-, -P(NR’)-, or -[(-O-C(R’) 2 -C(R’) 2 -) n -substitution.

[0441] In some embodiments, L is a covalent bond. In some embodiments, L is an optionally substituted divalent linear or branched C 1-100 aliphatic group, wherein one or more methylene units of said group are optionally and independently replaced. In some embodiments, L is an optionally substituted divalent linear or branched C 6-100 aryl aliphatic group, wherein one or more methylene units of said group are optionally and independently replaced. In some embodiments, L is an optionally substituted divalent linear or branched C with 1 - 20 heteroatoms 5-100 heteroaryl aliphatic group, wherein one or more methylene units of said group are optionally and independently replaced. In some embodiments, L is an optionally substituted divalent linear or branched C with 1 - 20 heteroatoms 1-100 heteroaliphatic group, wherein one or more methylene units of said group are optionally and independently replaced.

[0442] In some embodiments, the linker portion (e.g., L) is or comprises one or more polyethylene glycol units. In some embodiments, the linker portion is or comprises -(CH 2 CH 2 O) n -, where n is as described in the present disclosure. In some embodiments, one or more methylene units of L are independently replaced by -(CH 2 CH 2 O) n -. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

[0443] In some embodiments, the linker portion comprises one or more moieties that can be used to connect to other moieties, e.g., amino, carbonyl, etc. In some embodiments, the linker portion comprises one or more -NR'- groups, where R' is as described in the present disclosure. In some embodiments, -NR'- increases solubility. In some embodiments, -NR'- serves as a connection point to another moiety. In some embodiments, R' is -H. In some embodiments, one or more methylene units of L are independently replaced by -NR'- groups, where R' is as described in the present disclosure.

[0444] In some embodiments, the linker portion (e.g., L) comprises a -C(O)- group that can be used to connect to a moiety. In some embodiments, one or more methylene units of L are independently replaced by -C(O)-.

[0445] In some embodiments, the linker moiety is or comprises one or more ring moieties, e.g., one or more methylene units of L are replaced by -Cy-. In some embodiments, the linker moiety (e.g., L) comprises an aryl ring. In some embodiments, the linker moiety (e.g., L) comprises a heteroaryl ring. In some embodiments, the linker moiety (e.g., L) comprises an aliphatic ring. In some embodiments, the linker moiety (e.g., L) comprises a heterocyclic ring. In some embodiments, the linker moiety (e.g., L) comprises a polycycle. In some embodiments, the rings in the linker moiety (e.g., L) are 3- to 20-membered rings. In some embodiments, the ring is a 5-membered ring. In some embodiments, the ring is a 6-membered ring. In some embodiments, the rings in the linker are the products of a cycloaddition reaction (e.g., click chemistry and its variants) for joining different moieties together.

[0446] In some embodiments, the linker moiety (e.g., L) is or comprises

[0447] In some embodiments, the linker moiety is as described in Table 1. Additional linker moieties include, for example, those described for L 2 as those. In some embodiments, L is the L described in the present disclosure 1 . In some embodiments, L is the L described in the present disclosure 2 . In some embodiments, L is the L described in the present disclosure 3 . In some embodiments, L is the L described in the present disclosure b .

[0448] In some embodiments, L is

[0449] certain embodiments of the variable

[0450] By way of example, exemplary embodiments of the variables are described throughout the present disclosure. As will be understood by those skilled in the art, the embodiments of the different variables can be optionally combined.

[0451] As defined above and described herein, ABT is an antibody-binding portion.

[0452] In some embodiments, ABT is an antibody-binding portion.

[0453] In some embodiments, ABT is selected from those depicted in Table 1 below.

[0454] As defined above and described herein, L is a bivalent linker moiety that connects ABT to TBT.

[0455] In some embodiments, L is a bivalent linker moiety that connects ABT to TBT.

[0456] In some embodiments, L is selected from those depicted in Table 1 below.

[0457] As defined above and described herein, TBT is a target binding moiety.

[0458] In some embodiments, TBT is a target binding moiety.

[0459] In some embodiments, TBT is selected from those depicted in Table 1 below.

[0460] As defined above and described herein, R 1 , R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R 1 and R 1 ' optionally together with the intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3 ' optionally together with the intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; the R 5 group and the R 5’ group attached to the same carbon atom optionally together with the intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R 5 groups optionally together with the intervening atoms form a C 1-10 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -, or -Cy 1 -, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0461] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted group selected from C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 1 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 1 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic. In some embodiments, R 1 is an optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic. In some embodiments, R 1 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 1 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0462] In some embodiments, R 1 is

[0463] In some embodiments, R 1 is

[0464] In some embodiments, R 1 is

[0465] In some embodiments, R 1 and R 1 ' together with the intervening carbon atoms therebetween optionally form a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring. In some embodiments, R 1 and R 1 ' together with the intervening carbon atoms therebetween optionally form a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0466] In some embodiments, R 1 is selected from those depicted in Table 1 below.

[0467] In some embodiments, R is R as described in the present disclosure. 1 . In some embodiments, R a2 is R as described in the present disclosure. 1 . In some embodiments, R a3 is R as described in the present disclosure. 1 .

[0468] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted group selected from C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 3 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic. In some embodiments, R 3 is an optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic. In some embodiments, R 3 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0469] In some embodiments, R 3 is methyl. In some embodiments, R 3 is

[0470] In some embodiments, R 3 is

[0471] In some embodiments, R 3 is

[0472] In some embodiments, R 3 and R 3’Optionally together with the intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocyclic carbocycle. In some embodiments, R 3 and R 3’ optionally together with the intervening carbon atoms form a 4-8 membered saturated or partially unsaturated spirocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0473] In some embodiments, R 3 is selected from those depicted in Table 1 below.

[0474] In some embodiments, R is R 2 as described in the present disclosure. In some embodiments, R a2 is R 2 as described in the present disclosure. In some embodiments, R a3 is R 2 as described in the present disclosure.

[0475] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 5 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocycle. In some embodiments, R 5 is an optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 5 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0476] In some embodiments, R 5 is methyl. In some embodiments, R5 is

[0477] In some embodiments, R 5 is

[0478] In some embodiments, R 5 is

[0479] In some embodiments, R 5 is

[0480] In some embodiments, R 5 is

[0481] In some embodiments, R 5 and the R 5 ' group attached to the same carbon atom optionally form, together with the intervening carbon atoms, a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring. In some embodiments, R 5 and the R 5 ' group attached to the same carbon atom optionally form, together with the intervening carbon atoms, a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0482] In some embodiments, two R 5 groups together with the intervening atoms form a C 1-10 divalent straight-chain or branched-chain saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -, or -Cy 1 -, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0483] In some embodiments, two R 5 groups together with the intervening atoms form

[0484] In some embodiments, R 5 is selected from those depicted in Table 1 below.

[0485] In some embodiments, R is the R as described in the present disclosure 5 . In some embodiments, R a2 is the R as described in the present disclosure 5 . In some embodiments, R a3 is the R as described in the present disclosure 5 .

[0486] As defined above and described herein, R 1 ', R 3 ' and R 5 ' are each independently hydrogen or C 1-3 aliphatic.

[0487] In some embodiments, R 1’ is hydrogen. In some embodiments, R 1’ is C 1-3 aliphatic.

[0488] In some embodiments, R 1’ is methyl. In some embodiments, R 1’ is ethyl. In some embodiments, R 1’ is n-propyl. In some embodiments, R 1’ is isopropyl. In some embodiments, R 1’ is cyclopropyl.

[0489] In some embodiments, R 1’ is selected from those depicted in Table 1 below.

[0490] In some embodiments, R 3’ is hydrogen. In some embodiments, R 3’ is C 1-3 aliphatic.

[0491] In some embodiments, R 3’ is methyl. In some embodiments, R 3’ is ethyl. In some embodiments, R 3’ is n-propyl. In some embodiments, R 3’ is isopropyl. In some embodiments, R 3’ is cyclopropyl.

[0492] In some embodiments, R 3’ is selected from those depicted in Table 1 below.

[0493] In some embodiments, R 5’ is hydrogen. In some embodiments, R 5’ is C 1-3 aliphatic.

[0494] In some embodiments, R 5’ is methyl. In some embodiments, R 5’ is ethyl. In some embodiments, R 5’ is n-propyl. In some embodiments, R 5’ is isopropyl. In some embodiments, R 5’is cyclopropyl.

[0495] In some embodiments, R 5’ is selected from those depicted in Table 1 below.

[0496] As defined above and described herein, R 2 , R 4 and R 6 are each independently hydrogen or C 1-4 aliphatic, or: R 2 and R 1 optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 and R 3 optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or the R 6 group and its adjacent R 5 group optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0497] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is C 1-4 aliphatic. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is tert-butyl.

[0498] In some embodiments, R 2 and R 1 together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0499] In some embodiments, R 2 and R 1 together with the intervening atoms form

[0500] In some embodiments, R 2 is selected from those depicted in Table 1 below.

[0501] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-4 aliphatic. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is tert-butyl.

[0502] In some embodiments, R 4 and R 3 together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0503] In some embodiments, R 4 and R 3 together with the intervening atoms form

[0504] In some embodiments, R 4 is selected from those depicted in Table 1 below.

[0505] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1-4 aliphatic. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is n-propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-butyl. In some embodiments, R 6 is isobutyl. In some embodiments, R 6 is tert-butyl.

[0506] In some embodiments, R 6 group and its adjacent R 5 group together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0507] In some embodiments, R 6 group and its adjacent R 5The group, together with the intervening atoms therebetween, forms

[0508] In some embodiments, R 6 is selected from those depicted in Table 1 below.

[0509] In some embodiments, R is R as described in the present disclosure 1’ . In some embodiments, R a2 is R as described in the present disclosure 1’ . In some embodiments, R a3 is R as described in the present disclosure 1’ . In some embodiments, R is R as described in the present disclosure 3’ . In some embodiments, R a2 is R as described in the present disclosure 3’ . In some embodiments, R a3 is R as described in the present disclosure 3’ . In some embodiments, R is R as described in the present disclosure 2 . In some embodiments, R a2 is R as described in the present disclosure 2 . In some embodiments, R a3 is R as described in the present disclosure 2 . In some embodiments, R is R as described in the present disclosure 4 . In some embodiments, R a2 is R as described in the present disclosure 4 . In some embodiments, R a3 is R as described in the present disclosure 4 . In some embodiments, R is R as described in the present disclosure 6 . In some embodiments, R a2 is R as described in the present disclosure 6 . In some embodiments, R a3 is R as described in the present disclosure 6 .

[0510] As defined above and described herein, L 1 is a linking

[0511] In some embodiments, L 1 is

[0512] In some embodiments, L 1 is

[0513] In some embodiments, L 1 is selected from those depicted in Table 1 below.

[0514] As defined above and described herein, L 2 is a covalent bond or a C 1-10 divalent straight or branched chain saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units of said chain are independently and optionally substituted by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -,

[0515] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is a C 1-10 divalent straight or branched chain saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units of said chain are independently and optionally substituted by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -,

[0516] In some embodiments, L 2 is

[0517] In some embodiments, L 2 is selected from those depicted in Table 1 below.

[0518] In some embodiments, L is the L described in the present disclosure 2 .

[0519] As defined above and described herein, TBT is a target binding moiety.

[0520] In some embodiments, TBT is a target binding moiety.

[0521] In some embodiments, TBT is

[0522] In some embodiments, TBT is selected from those depicted in Table 1 below.

[0523] As defined above and described herein, m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0524] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0525] In some embodiments, m is selected from those depicted in Table 1 below.

[0526] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0527] In some embodiments, n is selected from those depicted in Table 1 below.

[0528] As defined above and described herein, each R 7 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R 7 groups and the R7' group attached to the same carbon atom optionally together with the intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocarbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spiroheterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0529] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is an optionally substituted group selected from C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 7 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is an optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R 7is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0530] In some embodiments, R 7 is methyl. In some embodiments, R 7 is

[0531] In some embodiments, R 7 is

[0532] In some embodiments, R 7 is

[0533] In some embodiments, R 7 is

[0534] In some embodiments, R 7 group and the R 7 ' group attached to the same carbon atom together with the intervening carbon atom form a 3-8 membered saturated or partially unsaturated spirocyclic carbocycle. In some embodiments, R 7 group and the R 7 ' group attached to the same carbon atom together with the intervening carbon atom form a 4-8 membered saturated or partially unsaturated spirocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0535] In some embodiments, R 7 is selected from those depicted in Table 1 below.

[0536] As defined above and described herein, each R 7 ' is independently hydrogen or C 1-3 aliphatic.

[0537] In some embodiments, R 7’ is hydrogen. In some embodiments, R 7’ is methyl. In some embodiments, R 7’ is ethyl. In some embodiments, R 7’ is n-propyl. In some embodiments, R 7’ is isopropyl.

[0538] In some embodiments, R 7’ is selected from those depicted in Table 1 below.

[0539] As defined above and described herein, each R 8 is independently hydrogen or C 1-4 aliphatic, or: R 8 groups and their adjacent R 7 groups optionally together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0540] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is C 1-4 aliphatic. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is isopropyl. In some embodiments, R 8 is n-butyl. In some embodiments, R 8 is isobutyl. In some embodiments, R 8 is tert-butyl.

[0541] In some embodiments, R 8 groups and their adjacent R 7 groups together with the intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0542] In some embodiments, R 8 groups and their adjacent R 7 groups together with the intervening atoms form

[0543] In some embodiments, R 8 is selected from those depicted in Table 1 below.

[0544] As defined above and described herein, R 9 is hydrogen, C 1-3 aliphatic or -C(O)C 1-3 aliphatic.

[0545] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is C 1-3 aliphatic. In some embodiments, R 9 is -C(O)C 1-3 aliphatic.

[0546] In some embodiments, R 9 is methyl. In some embodiments, R9 is ethyl. In some embodiments, R 9 is n-propyl. In some embodiments, R 9 is isopropyl. In some embodiments, R 9 is cyclopropyl.

[0547] In some embodiments, R 9 is -C(O)Me. In some embodiments, R 9 is -C(O)Et. In some embodiments, R 9 is -C(O)CH 2 CH 2 CH 3 In some embodiments, R 9 is -C(O)CH(CH 3 ) 2 In some embodiments, R 9 is -C(O)cyclopropyl.

[0548] In some embodiments, R 9 is selected from those depicted in Table 1 below.

[0549] In some embodiments, R is R as described in the present disclosure 7 In some embodiments, R a2 is R as described in the present disclosure 7 In some embodiments, R a3 is R as described in the present disclosure 7 In some embodiments, R is R as described in the present disclosure 7’ In some embodiments, R a2 is R as described in the present disclosure 7’ In some embodiments, R a3 is R as described in the present disclosure 7’ In some embodiments, R is R as described in the present disclosure 8 In some embodiments, R a2 is R as described in the present disclosure 8 In some embodiments, R a3 is R as described in the present disclosure 8 In some embodiments, R is R as described in the present disclosure 8’ In some embodiments, R a2 is R as described in the present disclosure 8’ In some embodiments, R a3 is R as described in the present disclosure 8’。In some embodiments, R is R as described in the present disclosure 9 。In some embodiments, R a2 is R as described in the present disclosure 9 。In some embodiments, R a3 is R as described in the present disclosure 9 。

[0550] As defined above and described herein, L 3 is a linking

[0551] In some embodiments, L 3 is a linking

[0552] In some embodiments, L 3 is

[0553] In some embodiments, L 3 is selected from those depicted in Table 1 below.

[0554] In some embodiments, L is L as described in the present disclosure 3 。

[0555] As defined above and described herein, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0556] In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. In some embodiments, o is 6. In some embodiments, o is 7. In some embodiments, o is 8. In some embodiments, o is 9. In some embodiments, o is 10.

[0557] In some embodiments, o is selected from those depicted in Table 1 below.

[0558] In certain embodiments, a useful agent (e.g., an ARM) is a compound of Formula II, wherein L 2 is

[0560] or a pharmaceutically acceptable salt thereof, wherein individually and in combination, L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m are each as defined above and as described in the embodiments herein.

[0561] In certain embodiments, a useful agent (e.g., an ARM) is a compound of Formula II, wherein L 2 is

[0563] or a pharmaceutically acceptable salt thereof, wherein, individually and in combination, L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m are each as defined above and as described in the embodiments herein.

[0564] In certain embodiments, a useful agent (e.g., an ARM) is a compound of Formula II, wherein L 2 is

[0566] or a pharmaceutically acceptable salt thereof, wherein, individually and in combination, L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m are each as defined above and as described in the embodiments herein.

[0567] In certain embodiments, a useful agent (e.g., an ARM) is a compound of Formula II, wherein L 2 is

[0569] or a pharmaceutically acceptable salt thereof, wherein, individually and in combination, L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m are each as defined above and as described in the embodiments herein.

[0570] In certain embodiments, a useful agent (e.g., an ARM) is a compound of Formula II, wherein L 2 is

[0572] or a pharmaceutically acceptable salt thereof, wherein, individually and in combination, L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m are each as defined above and as described in the embodiments herein.

[0573] In certain embodiments, a useful agent (e.g., an ARM) is a compound of Formula II, wherein L 2 is

[0575] or a pharmaceutically acceptable salt thereof, wherein, individually and in combination, L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m are each as defined above and as described in the embodiments herein.

[0576] In some embodiments, R a1 is R as described in the present disclosure. In some embodiments, R a1 is optionally substituted C 1-4 aliphatic.

[0577] In some embodiments, L a1 is L as described in the present disclosure a . In some embodiments, L a1 is a covalent bond.

[0578] In some embodiments, L a2 is L as described in the present disclosure a . In some embodiments, L a2 is a covalent bond.

[0579] In some embodiments, L a is a covalent bond. In some embodiments, L a is selected from C 1 -C 10 aliphatic or C 1 -C 10 with 1-5 heteroatomsAn optionally substituted divalent heteroaliphatic group, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, or -C(O)O-. In some embodiments, L a is selected from C 1 -C 5 aliphatic or C with 1-5 heteroatoms 1 -C 5 An optionally substituted divalent heteroaliphatic group, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, or -C(O)O-. In some embodiments, L a is an optionally substituted divalent C 1 -C 5 aliphatic, wherein one or more methylene units of said group are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R’)-, -C(O)S-, or -C(O)O-. In some embodiments, L a is an optionally substituted divalent C 1 -C 5 aliphatic. In some embodiments, L a is an optionally substituted C with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1 -C 5 heteroaliphatic.

[0580] In some embodiments, R a2 is R as described in the present disclosure. In some embodiments, R a2 is the side chain of a natural amino acid. In some embodiments, R a3 is R as described in the present disclosure. In some embodiments, R a3 is the side chain of a natural amino acid. In some embodiments, R 2a and R 3a one of them is hydrogen.

[0581] In some embodiments, each -Cy- is independently an optionally substituted divalent group selected from a C 3-20 alicyclic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted ring as described in the present disclosure, for example for R and Cy L but is a divalent ring.

[0582] In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- contains a saturated cyclic moiety. In some embodiments, -Cy- contains a partially unsaturated cyclic moiety. In some embodiments, -Cy- contains an aromatic cyclic moiety. In some embodiments, -Cy- contains a combination of saturated, partially unsaturated, and / or aromatic cyclic moieties. In some embodiments, -Cy- is 3-membered. In some embodiments, -Cy- is 4-membered. In some embodiments, -Cy- is 5-membered. In some embodiments, -Cy- is 6-membered. In some embodiments, -Cy- is 7-membered. In some embodiments, -Cy- is 8-membered. In some embodiments, -Cy- is 9-membered. In some embodiments, -Cy- is 10-membered. In some embodiments, -Cy- is 11-membered. In some embodiments, -Cy- is 12-membered. In some embodiments, -Cy- is 13-membered. In some embodiments, -Cy- is 14-membered. In some embodiments, -Cy- is 15-membered. In some embodiments, -Cy- is 16-membered. In some embodiments, -Cy- is 17-membered. In some embodiments, -Cy- is 18-membered. In some embodiments, -Cy- is 19-membered. In some embodiments, -Cy- is 20-membered.

[0583] In some embodiments, -Cy- is an optionally substituted divalent C 3-20 alicyclic ring. In some embodiments, -Cy- is an optionally substituted divalent saturated C 3-20 alicyclic ring. In some embodiments, -Cy- is an optionally substituted divalent partially unsaturated C 3-20 alicyclic ring. In some embodiments, -Cy-H is an optionally substituted alicyclic as described in the present disclosure, e.g., an alicyclic embodiment of R.

[0584] In some embodiments, -Cy- is an optionally substituted C 6-20 aryl ring. In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene. In some embodiments, -Cy- is an optionally substituted 1,3-phenylene. In some embodiments, -Cy- is an optionally substituted 1,4-phenylene. In some embodiments, -Cy- is an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an optionally substituted aryl as described in the present disclosure, e.g., an aryl embodiment of R.

[0585] In some embodiments, -Cy- is an optionally substituted divalent 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-H is an optionally substituted heteroaryl as described in the present disclosure, e.g., a heteroaryl embodiment of R. In some embodiments, -Cy- is

[0586] In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 3- to 6-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclic group having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclic group having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted saturated divalent heterocyclic group. In some embodiments, -Cy- is an optionally substituted partially unsaturated divalent heterocyclic group. In some embodiments, -Cy-H is an optionally substituted heterocyclic group as described in the present disclosure, for example, a heterocyclic group embodiment of R.

[0587] In some embodiments, each Xaa is independently an amino acid residue. In some embodiments, each Xaa is independently an amino acid residue of an amino acid of formula A-I.

[0588] In some embodiments, t is 0. In some embodiments, t is 1 - 50. In some embodiments, t is z as described in the present disclosure.

[0589] In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, z is 20. In some embodiments, z is greater than 20.

[0590] In some embodiments, R cis R' as described in the present disclosure. In some embodiments, R c is R as described in the present disclosure. In some embodiments, R c is -N(R') 2 , where each R' is independently as described in the present disclosure. In some embodiments, R c is -NH 2 . In some embodiments, R c is R-C(O)-, where R is as described in the present disclosure.

[0591] In some embodiments, a is 1. In some embodiments, a is 2 - 100. In some embodiments, a is 5. In some embodiments, a is 10. In some embodiments, a is 20. In some embodiments, a is 50.

[0592] In some embodiments, b is 1. In some embodiments, b is 2 - 100. In some embodiments, b is 5. In some embodiments, b is 10. In some embodiments, b is 20. In some embodiments, b is 50.

[0593] In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0594] In some embodiments, a2 is 0. In some embodiments, a2 is 1.

[0595] In some embodiments, L b is L as described in the present disclosure a . In some embodiments, L b contains -Cy-. In some embodiments, L b contains a double bond. In some embodiments, L b contains -S-. In some embodiments, L b contains -S-S-. In some embodiments, L b contains -C(O)-N(R')-.

[0596] In some embodiments, R' is -R, -C(O)R, -C(O)OR, or -S(O) 2 R, where R is as described in the present disclosure. In some embodiments, R' is R, where R is as described in the present disclosure. In some embodiments, R' is -C(O)R, where R is as described in the present disclosure. In some embodiments, R' is -C(O)OR, where R is as described in the present disclosure. In some embodiments, R' is -S(O) 2R, where R is as described in the present disclosure. In some embodiments, R' is hydrogen. In some embodiments, R' is not hydrogen. In some embodiments, R' is R, where R is an optionally substituted C 1-20 aliphatic. In some embodiments, R' is R, where R is an optionally substituted C 1-20 heteroaliphatic. In some embodiments, R' is R, where R is an optionally substituted C 6-20 aryl. In some embodiments, R' is R, where R is an optionally substituted C 6-20 arylalkyl. In some embodiments, R' is R, where R is an optionally substituted C 6-20 arylheteroaliphatic. In some embodiments, R' is R, where R is an optionally substituted 5- to 20-membered heteroaryl as described in the present disclosure. In some embodiments, R' is R, where R is an optionally substituted 3- to 20-membered heterocyclic group as described in the present disclosure. In some embodiments, two or more R's are R and optionally and independently together form an optionally substituted ring as described in the present disclosure.

[0597] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 arylalkyl, C with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 arylheteroaliphatic, a 5- to 30-membered heteroaryl with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 30-membered heterocyclic group with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or

[0598] two R groups optionally and independently together form a covalent bond, or:

[0599] two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring, which has 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom; or

[0600] Two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring, which monocyclic, bicyclic or polycyclic ring has 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms.

[0601] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 arylalkyl, C with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3- to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0602] Two R groups optionally and independently together form a covalent bond, or:

[0603] Two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring, which monocyclic, bicyclic or polycyclic ring has 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atom;

[0604] Two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring, which monocyclic, bicyclic or polycyclic ring has 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms.

[0605] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-20 aliphatic, C with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-20 heteroaliphatic, C 6-20 aryl, C 6-20 arylalkyl, C with 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-20 arylheteroaliphatic, a 5- to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3- to 20-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0606] The two R groups optionally and independently together form a covalent bond, or:

[0607] Two or more R groups on the same atom optionally and independently together with said atom form an optionally substituted 3- to 20-membered monocyclic, bicyclic or polycyclic ring, which monocyclic, bicyclic or polycyclic ring has 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to said atom;

[0608] Two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted 3- to 20-membered monocyclic, bicyclic or polycyclic ring, which monocyclic, bicyclic or polycyclic ring has 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms.

[0609] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 arylalkyl, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0610] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-20 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-20 heteroaliphatic, C 6-20 aryl, C 6-20 arylalkyl, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-20 arylheteroaliphatic, 5- to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 20-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0611] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is an optionally substituted group selected from C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 heteroaliphatic, C 6-30An aryl group, a 5-30-membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-30-membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0612] In some embodiments, R is hydrogen or an optionally substituted group selected from C 1-20 An aliphatic group, a phenyl group, a 3-7-membered saturated or partially unsaturated carbocyclic ring, an 8-10-membered bicyclic saturated ring, partially unsaturated ring, or aryl ring, a 5-6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0613] In some embodiments, R is an optionally substituted C 1-30 An aliphatic group. In some embodiments, R is an optionally substituted C 1-20 An aliphatic group. In some embodiments, R is an optionally substituted C 1-15 An aliphatic group. In some embodiments, R is an optionally substituted C 1-10 An aliphatic group. In some embodiments, R is an optionally substituted C 1-6 An aliphatic group. In some embodiments, R is an optionally substituted C 1-6 An alkyl group. In some embodiments, R is an optionally substituted hexyl, pentyl, butyl, propyl, ethyl, or methyl group. In some embodiments, R is an optionally substituted hexyl group. In some embodiments, R is an optionally substituted pentyl group. In some embodiments, R is an optionally substituted butyl group. In some embodiments, R is an optionally substituted propyl group. In some embodiments, R is an optionally substituted ethyl group. In some embodiments, R is an optionally substituted methyl group. In some embodiments, R is a hexyl group. In some embodiments, R is a pentyl group. In some embodiments, R is a butyl group. In some embodiments, R is a propyl group. In some embodiments, R is an ethyl group. In some embodiments, R is a methyl group. In some embodiments, R is an isopropyl group. In some embodiments, R is a n-propyl group. In some embodiments, R is a tert-butyl group. In some embodiments, R is a sec-butyl group. In some embodiments, R is a n-butyl group. In some embodiments, R is -(CH 2 ) 2 CN.

[0614] In some embodiments, R is an optionally substituted C 3-30 An alicyclic group. In some embodiments, R is an optionally substituted C 3-20alicyclic. In some embodiments, R is optionally substituted C 3-10 alicyclic. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0615] In some embodiments, R is an optionally substituted 3- to 30-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted cycloheptyl. In some embodiments, R is cycloheptyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0616] In some embodiments, when R is or comprises a ring structure (e.g., cycloaliphatic, cycloheteroaliphatic, aryl, heteroaryl, etc.), the ring structure can be monocyclic, bicyclic, or polycyclic. In some embodiments, R is or comprises a monocyclic structure. In some embodiments, R is or comprises a bicyclic structure. In some embodiments, R is or comprises a polycyclic structure.

[0617] In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 cycloheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms 1-20 cycloheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, or silicon (optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, or selenium) 1-20 cycloheteroaliphatic. In some embodiments, R is optionally substituted C 1-30 cycloheteroaliphatic, which comprises 1 to 10 groups independently selected from the following:

[0618] In some embodiments, R is an optionally substituted C 6-30 aryl. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is a substituted phenyl.

[0619] In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic partially unsaturated ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic aryl ring. In some embodiments, R is an optionally substituted naphthyl.

[0620] In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0621] In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, R is a substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.

[0622] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0623] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted pyrrolyl, furyl, or thienyl group.

[0624] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom and an additional heteroatom selected from sulfur or oxygen. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0625] In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having four nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having three nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having two nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring having one nitrogen atom.

[0626] In certain embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0627] In some embodiments, R is a 3-30 membered heterocycle having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 membered heterocycle having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is a 3-30 membered heterocycle having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 membered heterocycle having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0628] In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5- to 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5- to 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-membered heterocycle having one heteroatom selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 4-membered heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0629] In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0630] In certain embodiments, R is an optionally substituted 5- to 6-membered partially unsaturated monocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted tetrahydropyridyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl.

[0631] In some embodiments, R is an optionally substituted 7- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted indolinyl. In some embodiments, R is an optionally substituted isoindolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroquinolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R is an optionally substituted azabicyclo[3.2.1]octyl.

[0632] In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0633] In some embodiments, R is an optionally substituted C 6-30 aryl aliphatic. In some embodiments, R is an optionally substituted C 6-20 aryl aliphatic. In some embodiments, R is an optionally substituted C 6-10 aryl aliphatic. In some embodiments, the aryl moiety of the aryl aliphatic has 6, 10, or 14 aryl carbon atoms. In some embodiments, the aryl moiety of the aryl aliphatic has 6 aryl carbon atoms. In some embodiments, the aryl moiety of the aryl aliphatic has 10 aryl carbon atoms. In some embodiments, the aryl moiety of the aryl aliphatic has 14 aryl carbon atoms. In some embodiments, the aryl moiety is an optionally substituted phenyl.

[0634] In some embodiments, R is an optionally substituted C 6-30 aryl heteroaliphatic having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted C 6-30 aryl heteroaliphatic having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted C 6-20 aryl heteroaliphatic having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted C 6-20 aryl heteroaliphatic having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted C 6-10 aryl heteroaliphatic having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted C 6-10 aryl heteroaliphatic.

[0635] In some embodiments, two R groups optionally and independently together form a covalent bond. In some embodiments, -C=O is formed. In some embodiments, -C=C- is formed. In some embodiments, -C≡C- is formed.

[0636] In some embodiments, two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted monocyclic, bicyclic or polycyclic ring having 3 to 30 members, the monocyclic, bicyclic or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted monocyclic, bicyclic or polycyclic ring having 3 to 20 members, the monocyclic, bicyclic or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted monocyclic, bicyclic or polycyclic ring having 3 to 10 members, the monocyclic, bicyclic or polycyclic ring having 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted monocyclic, bicyclic or polycyclic ring having 3 to 6 members, the monocyclic, bicyclic or polycyclic ring having 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted monocyclic, bicyclic or polycyclic ring having 3 to 5 members, the monocyclic, bicyclic or polycyclic ring having 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atom.

[0637] In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with the intervening atoms therebetween, an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 3 to 30 members, said monocyclic, bicyclic, or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with the intervening atoms therebetween, an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 3 to 20 members, said monocyclic, bicyclic, or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with the intervening atoms therebetween, an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 3 to 10 members, said monocyclic, bicyclic, or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with the intervening atoms therebetween, an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 3 to 10 members, said monocyclic, bicyclic, or polycyclic ring having from 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with the intervening atoms therebetween, an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 3 to 6 members, said monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form, together with the intervening atoms therebetween, an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 3 to 5 members, said monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms.

[0638] In some embodiments, the heteroatoms in the R group or in the structure formed by two or more R groups together are selected from oxygen, nitrogen, and sulfur. In some embodiments, the ring formed is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered ring. In some embodiments, the ring formed is a saturated ring. In some embodiments, the ring formed is a partially saturated ring. In some embodiments, the ring formed is an aromatic ring. In some embodiments, the ring formed contains a saturated ring moiety, a partially saturated ring moiety, or an aromatic ring moiety. In some embodiments, the ring formed contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the ring formed contains no more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the aromatic ring atoms are selected from carbon, nitrogen, oxygen, and sulfur.

[0639] In some embodiments, the ring formed by two or more R groups (or two or more groups selected from R and variables that can be R) together is C 3-30 alicyclic, C 6-30 aryl, a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or a 3- to 30-membered heterocyclic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; the ring is as described for R, but is divalent or polyvalent.

[0640] Exemplary compounds of the present invention are listed in Table 1 below.

[0641] Table 1. Exemplary Compounds

[0658] In some embodiments, useful ARMs are the compounds listed in Table 1 above or pharmaceutically acceptable salts thereof.

[0659] 5. Exemplary methods for preparing immune cells and ARM agents

[0660] A variety of techniques in the art can be used to prepare immune cells, for example, the NK cells and agents of the present disclosure. Certain methods (including isolation, purification, pre-activation, characterization, evaluation, etc.) are described in the following references: Romee et al., Blood 120, 4751-4760, (2012); Leong et al., Biol. Blood Marrow Transplant. 20, 463-473 (2014); Romee et al., Sci Transl Med. 2016 Sep 21; 8(357):357ra123.doi:10.1126 / scitranslmed.aaf2341; and so on.

[0661] Agents such as ARM can be prepared, for example, by the synthetic methods exemplified in the examples.

[0662] For example, in some embodiments, useful compounds (e.g., ARM) are constructed by cycloaddition reactions (e.g., click chemistry or variants thereof).

[0663] In some embodiments, compounds that can be used, for example, to prepare the agents of the present disclosure (e.g., ARM) have the structure of Formula IV:

[0665] or a salt thereof, wherein

[0666] ABT is an antibody binding moiety;

[0667] L is a linker moiety;

[0668] R d is -L a -R’, where R d contains -C≡C- or -N 3 ;

[0669] Each L a is independently a covalent bond or is an optionally substituted divalent group selected from C 1 -C 20 aliphatic or C with 1-5 heteroatoms 1 -C 20 heteroaliphatic, wherein one or more methylene units of the group are optionally and independently replaced by -C(R’) 2 -, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O) 2 -, -S(O) 2replaced by -N(R’)-, -C(O)S-, or -C(O)O-;

[0670] each -Cy- is independently an optionally substituted divalent group selected from C 3-20 alicyclic ring, C 6-20 aryl ring, 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon;

[0671] each R' is independently -R, -C(O)R, -COR, or -SO 2 R; 2 R;

[0672] each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 arylalkyl, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or

[0673] two R groups optionally and independently together form a covalent bond, or:

[0674] two or more R groups on the same atom optionally and independently together with the atom form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom; or

[0675] two or more R groups on two or more atoms optionally and independently together with the intervening atoms form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms.

[0676] In some embodiments, for example, compounds useful for preparing the agents (e.g., ARM) of the present disclosure have the structure of Formula IV-a:

[0678] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0679] In some embodiments, compounds, such as those useful for preparing the agents of the present disclosure (e.g., ARMs), have the structure of Formula IV-b:

[0680] R c -(Xaa) z -L-R d ,

[0681] IV-b

[0682] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0683] In some embodiments, compounds, such as those useful for preparing the agents of the present disclosure (e.g., ARMs), have the structure of Formula IV-c:

[0685] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0686] In some embodiments, compounds, such as those useful for preparing the agents of the present disclosure (e.g., ARMs), have the structure of Formula IV-d:

[0688] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0689] In some embodiments, compounds, such as those useful for preparing the agents of the present disclosure (e.g., ARMs), have the structure of Formula V:

[0691] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0692] In some embodiments, methods for preparing a compound (e.g., an ARM) include the steps of:

[0693] providing a first compound of Formula IV, IV-a, IV-b, IV-c, or IV-d or a salt thereof, wherein the compound comprises a first reactive moiety;

[0694] providing a second compound of Formula V or a salt thereof that comprises a second reactive moiety; and

[0695] reacting the first compound with the second compound, wherein the first reactive moiety reacts with the second reactive moiety by a cycloaddition reaction.

[0696] Many cycloaddition reactions can be used in accordance with the present disclosure. In some embodiments, the cycloaddition reaction is a [4+2] reaction. In some embodiments, the cycloaddition reaction is a [3+2] reaction. In some embodiments, the [3+2] reaction is a click chemical reaction. In some embodiments, the first reactive moiety is -C≡C- and the second reactive moiety is -N 3 . In some embodiments, the first reactive moiety is -N 3 and the second reactive moiety is -C≡C-.

[0697] 6. Uses, Formulations, and Administrations

[0698] Pharmaceutically acceptable compositions

[0699] In some embodiments, the present disclosure provides a composition comprising immune cells (e.g., pre-activated memory-like NK cells) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a composition comprising an agent and its pharmaceutically acceptable derivatives and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a composition comprising immune cells and an agent and its pharmaceutically acceptable derivatives and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the immune cells and the useful agent (e.g., ARM) are provided in separate compositions. In some embodiments, the immune cells and the useful agent (e.g., ARM) are provided in the same composition.

[0700] In many embodiments, the immune cells are administered in an amount sufficient to provide a therapeutic benefit without serious side effects. For example, in some embodiments, the immune cells are administered at 0.01 - 100, 0.1 - 50, 0.1 - 20, 0.1 - 10, 0.05, 0.1, 0.2, 0.3, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90 million cells / kg of subject body weight.

[0701] An agent (e.g., ARM) is typically administered in an amount effective to selectively redirect an endogenous antibody (e.g., an endogenous antibody) and / or a fragment thereof to a target cell (e.g., a cancer cell) to induce antibody-directed, cell-mediated immunity (e.g., cytotoxicity). In certain embodiments, the amount of the compound in the compositions of the present disclosure is such that they effectively redirect an endogenous antibody selectively to cancer cells, thereby inducing antibody-directed, cell-mediated cytotoxicity in a biological sample or a subject. In some embodiments, the amount is 0.01 - 100 mg / kg body weight. In some embodiments, the amount is 0.01 - 50 mg / kg body weight. In some embodiments, the amount is from about 1 mg / kg to about 25 mg / kg.

[0702] In some embodiments, a pharmaceutically acceptable carrier, adjuvant, or vehicle is a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin. In some embodiments, immune cells can be provided in a suitable medium.

[0703] In some embodiments, the agent can be provided as a pharmaceutically acceptable derivative, which can be a non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that is capable of directly or indirectly providing the agent upon administration to a recipient.

[0704] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. In some embodiments, parenteral administration includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Preferably, the composition comprising immune cells is administered intravenously. The sterile injectable form of the compositions of the present disclosure can be an aqueous or oily suspension. The suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0705] In some embodiments, the agent (e.g., ARM) is formulated into a composition for delayed and / or sustained release. Techniques for sustained release and / or slow absorption are widely available in the art and can be used in accordance with the present disclosure.

[0706] In some embodiments, mild fixed oils can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxylated forms. Such oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers can also be used for formulation purposes, which are typically used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms.

[0707] The pharmaceutically acceptable compositions of the agents (e.g., ARM) of the present disclosure can be administered orally in any orally acceptable dosage form (e.g., capsules, tablets, aqueous suspensions, or solutions). In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate can also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifying and / or suspending agent. If desired, certain sweetening, flavoring, or coloring agents can also be added.

[0708] Solid dosage forms for oral administration, for example, include capsules, tablets, pills, powders, and granules. In some embodiments, the agent to be delivered (e.g., ARM) is mixed with at least one pharmaceutically acceptable inert excipient or carrier (such as sodium citrate or calcium hydrogen phosphate) and / or the following: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin wax; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0709] The solid compositions can also be used as fillers in soft and hard gelatin capsules, which use excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycols. In some embodiments, solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings and other coatings well known in the art of pharmaceutical formulation). In some embodiments, the solid compositions can optionally contain emulsifying agents and can release the agent to be delivered only or preferentially at a certain site of the subject (e.g., a certain site of the intestine), optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0710] In some embodiments, the agent (e.g., ARM) can be in microencapsulated form with one or more of the excipients described above. In some embodiments, solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings, controlled release coatings, and other coatings well known in the art of pharmaceutical formulation). In such solid dosage forms, the agent to be delivered can be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Such dosage forms can also contain additional substances as in normal practice, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In some embodiments, in the case of capsules, tablets, and pills, the dosage form can contain buffering agents.

[0711] Alternatively, a pharmaceutically acceptable composition can be administered rectally in the form of a suppository. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature and liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0712] The pharmaceutically acceptable compositions of the invention can also be administered topically, especially when the therapeutic target comprises an area or organ which is readily accessible by topical administration, including diseases of the eye, skin or lower intestine. Suitable topical formulations can be readily prepared for each of these areas or organs.

[0713] For topical administration, the pharmaceutically acceptable compositions can be formulated in a suitable ointment which contains the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream which contains the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0714] For ophthalmic use, the pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution (with or without a preservative such as benzalkonium chloride) in isotonic, pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0715] The pharmaceutically acceptable compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, absorption promoters which enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents, and can be made as solutions in saline.

[0716] Pharmaceutically acceptable compositions of the agent (e.g., ARM) can be formulated for oral administration. Such formulations can be administered with food or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food.

[0717] It should also be understood that the specific dosage and treatment regimen for a particular subject will depend on a variety of factors, such as the activity of the specific immune cells and / or agents used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated, among others.

[0718] Use

[0719] Among other things, the present disclosure encompasses the recognition that certain immune cells, such as pre-activated memory-like NK cells, have improved properties and / or activities against their targets (e.g., cancer cells) and can be particularly effective in treating conditions, disorders, or diseases (such as cancer); however, such immune cells may also cause more severe side effects, such as off-target effects, for example, due to their increased cytotoxicity. Thus, in some embodiments, the present disclosure provides techniques for exposing a subject to both such immune cells and an agent (e.g., an ARM), which can promote the targeting of the immune cells to the desired target (e.g., cancer cells) and reduce the side effects of such immune cell therapies.

[0720] In some embodiments, the useful agent selectively directs an antibody (e.g., an endogenous antibody) to diseased cells (e.g., cancer cells), thereby inducing and / or promoting an antibody-directed, cell-mediated immune response, such as cytotoxicity produced by immune cells (e.g., pre-activated memory-like NK cells (e.g., cytokine-induced memory-like NK cells)). In some embodiments, the recruited antibody includes one or more endogenous antibodies. In some embodiments, the recruited antibody is specific for one or more antigens. In some embodiments, the recruited antibody is specific for one or more peptide antigens or proteins. In some embodiments, the recruited antibodies are heterogeneous in that they are not antibodies against the same antigen or protein.

[0721] In some embodiments, the useful agent (e.g., an ARM) triggers, generates, encourages, and / or enhances one or more immune system activities against a target. In some embodiments, the immune system activity is or includes ADCC produced by NK cells. In some embodiments, the immune system activity is or includes ADCC produced by pre-activated memory-like NK cells (e.g., cytokine-induced memory-like NK cells). In some embodiments, the target is a cancer cell. In some embodiments, the target is a cancer cell in a subject.

[0722] As described herein, administering immune cells (such as pre-activated memory-like NK cells, e.g., cytokine-induced memory-like NK cells) and an agent (such as an ARM) exposes a subject to both. In some embodiments, the immune cells (or a dose thereof) are administered before the ARM agent (or a dose thereof). In some embodiments, the immune cells (or a dose thereof) are administered after the ARM agent (or a dose thereof). In some embodiments, the immune cells (or a dose thereof) are administered concurrently with the ARM agent (or a dose thereof). When administered concurrently, the immune cells and the ARM can be administered in one composition or as separate compositions. In some embodiments, the immune cells and the ARM are administered within 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of each other, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks. The immune cells and the agent (e.g., the ARM) can be administered independently as a single dose or multiple doses. In some embodiments, the administered immune cells (e.g., pre-activated memory-like NK cells) form a complex with the administered ARM together with a target (e.g., a cancer cell) and an antibody (or a fragment thereof) in a subject, wherein the antibody (or a fragment thereof) interacts with the immune cells and the ARM, and the ARM interacts with the antibody (or a fragment thereof) and the target (e.g., a cancer cell).

[0723] In some embodiments, "treating" as used herein includes reversing, alleviating, delaying the onset of, or inhibiting the progression of a disorder, condition, or disease or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have appeared. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a history of the symptoms and / or based on genetic or other predisposing factors). Treatment can also continue after symptoms have subsided, e.g., to prevent or delay their recurrence.

[0724] In some embodiments, the present invention provides methods for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is cancer. Among other aspects, the provided technologies (e.g., compounds, compositions, methods, etc.) are particularly useful for preventing and / or treating cancer.

[0725] In some embodiments, cancer is a pathological process that results in the formation and growth of a cancerous or malignant tumor, which is abnormal tissue that grows by cell proliferation, typically growing faster than normal tissue and continuing to grow after the stimuli that initiated the new growth have ceased. Malignant tumors may show partial or complete loss of structural organization and functional coordination with normal tissue, and most malignant tumors invade surrounding tissues, metastasize to several sites, and are likely to recur and cause death of the patient unless adequately treated. In some embodiments, as used herein, the term neoplasia includes all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematological tumors, ascitic tumors, and solid tumors. Representative cancers include, for example, prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, renal cancer, brain cancer / CNS cancer, head and neck cancer, throat cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, larynx cancer, kidney cancer, and lymphoma, among others, which can be treated with one or more compounds according to the present invention.

[0726] In some embodiments, the cancer is leukemia. In some embodiments, the techniques provided are particularly useful for treating leukemia. In some embodiments, the techniques provided are particularly useful for treating acute myeloid leukemia (AML). In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is melanoma.

[0727] In some embodiments, prior to administering the therapies of the present invention (e.g., exposure to administered pre-activated memory-like NK cells and ARM), the subject may have been treated with another therapy (e.g., chemotherapy, immunotherapy, surgery, etc.). In some embodiments, the subject is susceptible to, or has, recurrent or refractory cancer. In some embodiments, the subject is susceptible to, or has, recurrent or refractory leukemia. In some embodiments, the subject is susceptible to, or has, recurrent or refractory AML.

[0728] In some embodiments, a treatment can be administered to a subject undergoing a lymphodepletion regimen. In some embodiments, depletion of immunomodulatory elements (e.g., using cytotoxic agents or total body irradiation) can enhance the activity of the administered immune cells. In some embodiments, a cytotoxic agent, such as fludarabine, cyclophosphamide, and / or alemtuzumab, is administered to the subject.

[0729] Combination therapy

[0730] In certain embodiments, the provided technology (e.g., a technology comprising immune cells (e.g., memory-like NK cells) and an ARM) is administered in combination with one or more other therapies. In some embodiments, in addition to the immune cells (e.g., memory-like NK cells) and the ARM agent, another therapy is administered to the subject. In some embodiments, the subject has cancer, and such another therapy is a cancer therapy, e.g., chemotherapy, immunotherapy, surgery, etc.

[0731] Among other things, the techniques of the present disclosure, including immune cells (e.g., memory-like NK cells) and ARMs, can be used in combination with other therapies, i.e., such techniques can be administered simultaneously with, before, or after one or more other therapeutic agents or medical procedures, particularly for treating various cancers. In some embodiments, such techniques can be used in combination with other anti-proliferative compounds. In some embodiments, the therapeutic agents that can be used in combination are chemotherapeutic agents or anti-proliferative compounds. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone therapy drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapy drugs, and other anti-cancer agents. Additionally, the provided techniques can be used for the restoration of a patient's QOL together with, or in a mixture with, leukopenia (neutropenia) drugs, thrombocytopenia drugs, antiemetic drugs, and cancer pain drugs that are adjuvants for cancer treatment. In some embodiments, the therapeutic agent is an antibody. In some embodiments, the therapeutic agent is an immunomodulator. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells, wherein the agent is an antagonist that blocks a co-inhibitory pathway. In some embodiments, the immunomodulator is a checkpoint blocker. In some embodiments, the immunomodulator is an antibody that targets cell surface signaling proteins expressed by immune cells. In some embodiments, the immunomodulator is an antibody that targets a protein selected from the group consisting of PD-1, PD-L1, CTLA4, TIGIT, BTLA, TIM-3, LAG3, B7-H3, and B7-H4. In some embodiments, the immunomodulator is a PD-1 antibody (e.g., nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL328OA, etc.). In some embodiments, the immunomodulator is a PD-L1 antibody. In some embodiments, the immunomodulator is a CTLA4 antibody (e.g., ipilimumab). In some embodiments, the immunomodulator is a TIGIT antibody. In some embodiments, the immunomodulator is a BTLA antibody. In some embodiments, the immunomodulator is a Tim-3 antibody. In some embodiments, the immunomodulator is a LAG3 antibody. In some embodiments, the immunomodulator is a B7-H3 antibody. In some embodiments, the immunomodulator is a B7-H4 antibody. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells, wherein the agent is an agonist that participates in a co-stimulatory pathway. In some embodiments, such immunomodulators are or comprise antibodies that target co-stimulatory receptors. In some embodiments, the antibody activates a T cell co-stimulatory receptor.In some embodiments, the antibody targets a member of the tumor necrosis factor (TNF) receptor superfamily. In some embodiments, the antibody targets a protein selected from CD137 (4-1BB), CD357 (GITR, TNFRS18, AITR), CD134 (OX40), and CD40 (TNFRSF5). In some embodiments, the antibody is an anti-CD137 antibody (e.g., urelumab). In some embodiments, the antibody is an anti-CD357 antibody. In some embodiments, the antibody is an anti-CD40 antibody. In some embodiments, the antibody is an anti-CD134 antibody. Other exemplary T cell co-stimulatory and co-inhibitory receptors are described in Chen L, Flies DB., Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013, 13(4), 227-42, and Yao S et al., Advances in targeting cell surface signalling molecules for immune modulation. Nat. Rev. Drug Discov. 2013, 12(2), 136-40. In some embodiments, the therapeutic agent is an antibody that activates such stimulatory receptors or blocks such inhibitory receptors.

[0732] In some embodiments, for hematologic malignancies, a useful additional therapeutic agent for combination can be rituximab

[0733] In some embodiments, the disorder, condition or disease is diffuse large B cell lymphoma (DLBCL). In some embodiments, useful additional agents for combination for DLBCL are selected from rituximab

[0734] In another embodiment, the disorder, condition or disease is multiple myeloma. In some embodiments, useful additional agents for combination are selected from bortezomib

[0735] In another embodiment, the disorder, condition or disease is Waldenström macroglobulinemia. In some embodiments, useful additional therapeutic agents are selected from chlorambucil

[0736] In some embodiments, one or more other therapeutic agents for combination are or comprise tumor-specific immune cells. In some embodiments, the composition for combination comprises an immune-enhancing substance. Exemplary immune-enhancing substances that can be used in combination with the provided technology comprising immune cells and ARMs include various cytokines and tumor antigens. Cytokines that stimulate an immune response include, for example, GM-CSF, M-CSF, G-CSF, interferon-α, β, γ, IL-1, IL-2, IL-3, and IL-12, among others. Antibodies that block inhibitory receptors and / or activate stimulatory receptors (which are well known in the art and described herein, for example, B7 ligand derivatives, anti-CD3 antibodies, anti-CD28 antibodies, and anti-CTLA-4 antibodies) can improve the desired immune response. In some embodiments, the therapeutic agent for combination comprises or is a small molecule for immunomodulation. In some embodiments, the therapeutic agent is a small molecule that mediates anti-tumor immune activity. In some embodiments, the therapeutic agent is a small molecule that targets an enzyme directly involved in immunomodulation. In some embodiments, the therapeutic agent is an indoleamine 2,3-dioxygenase (IDO) inhibitor. In some embodiments, the therapeutic agent is an IDO1 inhibitor, such as, F001287, indoximod, NLG-919, and INCB024360. In some embodiments, the therapeutic agent is a tryptophan-2,3-dioxygenase (TDO) inhibitor. In some embodiments, the therapeutic agent is an IDO / TDO dual inhibitor. In some embodiments, the therapeutic agent is an IDO selective inhibitor. In some embodiments, in some other embodiments, the therapeutic agent is a TDO selective inhibitor. In some embodiments, the provided composition comprises an IDO inhibitor. In some embodiments, the provided composition comprises an IDO inhibitor.

[0737] In some embodiments, medical procedures that can be used in combination with the compounds, compositions, and methods include surgery, radiotherapy (e.g., γ-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioisotopes, etc.), endocrine therapy, biologic response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF), etc.), hyperthermia, cryotherapy, and adoptive T cell transfer (e.g., TIL therapy, transgenic TCR, CAR T cell therapy, etc.). In some embodiments, the medical procedure is surgery. In some embodiments, the medical procedure is radiotherapy.

[0738] In some embodiments, antiproliferative compounds that can be used in combination include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce the process of cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and other antiangiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors such as 17-AAG (17-allylamino geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide

[0739] In some embodiments, an antiestrogen is a compound that antagonizes the action of estrogen at the estrogen receptor level. In some embodiments, it is selected from tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. In some embodiments, the combination with a chemotherapeutic agent as an antiestrogen is particularly useful for the treatment of estrogen receptor-positive tumors such as breast tumors.

[0740] In some embodiments, an antiandrogen is a substance capable of inhibiting the biological effects of androgens. In some embodiments, it is bicalutamide (Casodex TM ). In some embodiments, the gonadorelin agonist is abarelix, goserelin or goserelin acetate.

[0741] In some embodiments, the topoisomerase I inhibitors are selected from topotecan, gemitecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.

[0742] In some embodiments, the topoisomerase II inhibitors are selected from anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunomycin, epirubicin, idarubicin and nemorubicin; mitoxantrone and losoxantrone of anthraquinones; and etoposide and teniposide of podophyllotoxins.

[0743] In some embodiments, the microtubule-acting agent is selected from microtubule-stabilizing compounds or microtubule-destabilizing compounds and tubulin polymerization inhibitors, e.g., taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine; and epothilones and their derivatives.

[0744] In some embodiments, the alkylating agent is cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel).

[0745] In some embodiments, the histone deacetylase inhibitor or HDAC inhibitor is a compound that inhibits histone deacetylase and has antiproliferative activity. In some embodiments, the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA). In some embodiments, HDAC inhibitors useful for combination are MS275, SAHA, FK228 (formerly FR901228), trichostatin A, or the compounds disclosed in US 6,552,065, e.g., N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof (especially the lactate).

[0746] In some embodiments, the antineoplastic antimetabolites are selected from 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.

[0747] In some embodiments, the platinum compound is carboplatin, cis-platin (or cisplatinum), or oxaliplatin.

[0748] In some embodiments, compounds that target / reduce protein or lipid kinase activity, or compounds that target / reduce protein or lipid phosphatase activity, or other anti-angiogenic compounds are protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors. For example, a) compounds that target, reduce or inhibit platelet-derived growth factor receptor (PDGFR) activity, such as compounds that target, reduce or inhibit PDGFR activity, especially compounds that inhibit the PDGF receptor, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) compounds that target, reduce or inhibit fibroblast growth factor receptor (FGFR) activity; c) compounds that target, reduce or inhibit insulin-like growth factor receptor I (IGF-IR) activity, such as compounds that target, reduce or inhibit IGF-IR activity, especially compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit Ret receptor tyrosine kinase activity; g) compounds that target, reduce or inhibit Kit / SCFR receptor tyrosine kinase activity, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib or nilotinib (AMN107), PD180970, AG957, NSC 680410, PD173955 from Parke Davis, or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK, and TEC family members, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine, ilmofosine, RO 318220 and RO 320432, GO 6976, lsis 3521, LY333531 / LY379196, isoquinoline compounds, FTI, PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, e.g., compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrosine phosphorylation inhibitors such as tyrosine phosphorylation inhibitor A23 / RG-50810, AG 99, tyrosine phosphorylation inhibitor AG 213, tyrosine phosphorylation inhibitor AG 1748, tyrosine phosphorylation inhibitor AG 490, tyrosine phosphorylation inhibitor B44, tyrosine phosphorylation inhibitor B44 (+) enantiomer, tyrosine phosphorylation inhibitor AG 555, AG 494, tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR 1 ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, e.g., compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family are especially compounds that inhibit members of the EGF receptor tyrosine kinase family (such as the EGF receptor, ErbB2, ErbB3 and ErbB4) or compounds, proteins or antibodies that bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM ), cetuximab (Erbitux TM) Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce or inhibit c-Met receptor activity, such as compounds that target, reduce or inhibit c-Met activity, especially compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and; and q) compounds that target, reduce or inhibit the signaling effect of the hedgehog protein (Hh) or smoothened receptor (SMO) pathway, including cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0749] In some embodiments, the PI3K inhibitor is a compound having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors that can be used in combination include ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictilisib, PF-4691502, BYL-719, datolisib, XL-147, XL-765, and elalisib.

[0750] In some embodiments, the BTK inhibitor is a compound having inhibitory activity against Bruton's tyrosine kinase (BTK), for example, AVL-292, ibrutinib, and the like.

[0751] In some embodiments, the SYK inhibitor is a compound having inhibitory activity against spleen tyrosine kinase (SYK), for example, PRT-062070, R-343, R-333, Excellair, PRT-062607, fostamatinib, and the like. Other examples of BTK inhibitory compounds can be found in WO 2008039218 and WO 2011090760.

[0752] Examples of SYK inhibitory compounds can be found in WO 2003063794, WO 2005007623, and WO 2006078846.

[0753] Examples of PI3K inhibitory compounds can be found in WO 2004019973, WO 2004089925, WO 2007016176, US8138347, WO 2002088112, WO 2007084786, WO 2007129161, WO 2006122806, WO 2005113554, and WO 2007044729.

[0754] Examples of JAK inhibitory compounds can be found in WO 2009114512, WO 2008109943, WO 2007053452, WO 2000142246, and WO 2007070514.

[0755] In some embodiments, the anti-angiogenic compound has an alternative mechanism of its activity, e.g., unrelated to protein or lipid kinase inhibition, e.g., thalidomide (Thalomid TM ), and TNP-470.

[0756] Examples of proteasome inhibitors that can be used in combination include bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0757] In some embodiments, the compound that targets, reduces, or inhibits protein or lipid phosphatase activity is an inhibitor of, e.g., phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives. In some embodiments, the compound that induces the process of cell differentiation is, e.g., retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ-, or δ-tocotrienol, etc.

[0758] In some embodiments, the cyclooxygenase inhibitor is selected from Cox-2 inhibitors, 5-alkyl-substituted 2-aryl aminophenylacetic acids and derivatives, such as celecoxib (Celebrex TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib, or 5-alkyl-2-aryl aminophenylacetic acid (such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid), lumiracoxib.

[0759] In some embodiments, the bisphosphonates are selected from etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. In some embodiments, the mTOR inhibitor is a compound that inhibits the mammalian target of rapamycin (mTOR) and has anti-proliferative activity, such as sirolimus

[0760] In some embodiments, the heparanase inhibitor targets, reduces, or inhibits heparan sulfate degradation. In some embodiments, it is PI-88. In some embodiments, the biological response modifier is a lymphokine or interferon.

[0761] In some embodiments, the inhibitor of Ras oncogenic isoforms (such as H-Ras, K-R...

Claims

1. Use of an antibody recruitment molecule (ARM) and a plurality of natural killer cells in the preparation of a medicament for inducing cell death of cancer cells, inhibiting cancer cell growth and / or reducing the number of cancer cells in a patient, wherein the ARM is a compound of the following formula: or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from multiple myeloma, leukemia, lymphoma and melanoma.

2. Use of an antibody recruitment molecule (ARM) in the preparation of a medicament for inducing cell death of cancer cells, inhibiting cancer cell growth and / or reducing the number of cancer cells in a patient, wherein the ARM is a compound of the following formula: or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from multiple myeloma, leukemia, lymphoma and melanoma.

3. Use of an antibody recruitment molecule (ARM) and a plurality of natural killer cells in the preparation of a medicament for treating a disorder, condition or disease, wherein the ARM is a compound of the following formula: or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from multiple myeloma, leukemia, lymphoma and melanoma.

4. Use according to any one of claims 1-3, wherein the cancer is selected from multiple myeloma, leukemia and lymphoma.

5. Use according to claim 1 or 3, wherein the medicament is for reducing the side effects of a treatment using natural killer cells in a subject.

6. Use according to claim 1 or 3, wherein the medicament is for reducing the toxicity of a treatment using natural killer cells.

7. Use according to claim 1 or 3, wherein the natural killer cells are memory-like natural killer cells.

8. Use according to claim 1 or 3, wherein the natural killer cells are cytokine-induced memory-like natural killer cells induced by IL-12, IL-15 and IL-18.

9. Use according to claim 1 or 3, wherein the natural killer cells and the ARM are administered simultaneously in a composition.

10. Use according to claim 1 or 3, wherein the natural killer cells are administered before or after the ARM.

11. Use of an antibody recruitment molecule (ARM), a plurality of natural killer cells and an antibody in the preparation of a medicament for treating a disorder, condition or disease, wherein the ARM is a compound of the following formula: or a pharmaceutically acceptable salt thereof, and wherein the disorder, condition or disease is a cancer selected from multiple myeloma, leukemia, lymphoma and melanoma.

12. A combination product comprising: a plurality of natural killer cells; and an antibody recruitment molecule (ARM), wherein the ARM is a compound of the following formula: or a pharmaceutically acceptable salt thereof.

13. The combination product according to claim 12, wherein the natural killer cells are according to claim 14. The combination product according to claim 13, further comprising an antibody.

15. A composition comprising: a plurality of natural killer cells; and an antibody recruitment molecule (ARM), wherein the ARM is a compound of the following formula: or a pharmaceutically acceptable salt thereof.

16. The composition according to claim 15, further comprising an antibody.

17. An antibody recruitment molecule (ARM) having the following formula, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the antibody recruitment molecule (ARM) according to claim 17 and a pharmaceutically acceptable excipient.

Images